Type ii raf kinase inhibitors

ABSTRACT

The present invention relates to novel compounds which are able to modulate b-raf kinases, and the use of such compounds in the treatment of various diseases, disorders or conditions.

RELATED APPLICATIONS

This application is a continuation of and claims priority under 35U.S.C. §120 to U.S. application, U.S. Ser. No. 13/519,826, filed Nov. 1,2012, which is a national stage filing under 35 U.S.C. §371 ofinternational PCT application, PCT/US2010/062310, filed Dec. 29, 2010,which claims priority under 35 U.S.C. §119(e) to U.S. provisional patentapplication, U.S. Ser. No. 61/290,884, filed Dec. 29, 2009. The entirecontents of the above-referenced applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to novel compounds which are able toinhibit b-raf and b-raf mutations, and the use of such compounds in thetreatment of various diseases, disorders or conditions.

BACKGROUND OF THE INVENTION

Receptor tyrosine kinases and serine/threonine kinases have beenimplicated in cellular signaling pathways that control cell function,division, growth, differentiation, and apoptosis through reversiblephosphorylation of the hydroxyl groups of tyrosine or serine andthreonine residues, respectively, in proteins. In signal transduction,for example, extracellular signals are transduced via membrane receptoractivation, with amplification and propagation using a complexchoreography of cascades of protein phosphorylation, and proteindephosphorylation events to avoid uncontrolled signaling. Thesesignaling pathways are highly regulated, often by complex andintermeshed kinase pathways where each kinase may itself be regulated byone or more other kinases and protein phosphatases. The biologicalimportance of these finely tuned systems is such that a variety of cellproliferative disorders have been linked to defects in one or more ofthe various cell signaling pathways mediated by tyrosine orserine/threonine kinases.

Receptor tyrosine kinases (RTKs) catalyze phosphorylation of certaintyrosyl amino acid residues in various proteins, including themselves,which govern cell growth, proliferation and differentiation.

Downstream of the several RTKs lie several signaling pathways, includingthe Ras-Raf-MEK-ERK kinase pathway. It is currently understood thatactivation of Ras GTPase proteins in response to growth factors,hormones, cytokines, etc. stimulates phosphorylation and activation ofRaf kinases. These kinases then phosphorylate and activate theintracellular protein kinases MEK1 and MEK2, which in turn phosphorylateand activate other protein kinases, ERK1 and 2. This signaling pathway,also known as the mitogen-activated protein kinase (MAPK) pathway orcytoplasmic cascade, mediates cellular responses to growth signals. Theultimate function of this is to link receptor activity at the cellmembrane with modification of cytoplasmic or nuclear targets that governcell proliferation, differentiation, and survival. Mutations in variousRas GTPases and the B-Raf kinase have been identified that can lead tosustained and constitutive activation of the MAPK pathway, ultimatelyresulting in increased cell division and survival. As a consequence ofthis, these mutations have been strongly linked with the establishment,development, and progression of a wide range of human cancers. Thebiological role of the Raf kinases, and specifically that of B-Raf, insignal transduction is described in Davies, H., et al., Nature (2002)9:1-6; Garnett, M. J. & Marais, R., Cancer Cell (2004) 6:313-319;Zebisch, A. & Troppmair, J., Cell. Mol. Life. Sci. (2006) 63:1314-1330;Midgley, R. S. & Kerr, D. J., Crit. Rev. One/Hematol. (2002) 44:109-120;Smith, R. A., et al., Curr. Top. Med. Chem. (2006) 6:1071-1089; andDownward, J., Nat. Rev. Cancer (2003) 3:11-22.

The “Erk pathway” is an intracellular signal transduction pathway usedby nearly all types of human cells to translate extracellular signals tocellular decisions, including proliferation, differentiation,senescence, or apoptosis (Wellbrock et al., Nat. Rev. Mol. Cell Biol.11:875-885 (2004)). One of the invariant components of this pathway isthe Ras GTPase, which receives signals from membrane receptors andactivates the Raf protein kinases, which activate the Mek proteinkinases, which in turn activate the Erk protein kinases. Activated Erkkinases phosphorylate a number of nuclear and cytoplasmic targets toinitiate various cellular decisions. The biological importance of Raf inthe Erk pathway is underscored by the finding that mutated forms of Rafare associated with certain human malignancies (see e.g. Monia et al.,Nature Medicine 2:668-675 (1996); Davies et al., Nature 417:949-954(2002)). Three distinct genes have been identified in mammals thatencode Raf proteins; a-Raf, b-Raf and c-Raf (also known as Raf-1) andisoformic variants that result from differential splicing of mRNA areknown (Chong et al., EMBO J. 20:3716-3727 (2001)). The Erk pathway ismutationally activated in a number of human cancers, most often bymutation of the Ras or b-Raf genes. Mutations in Ras and b-Raf genesgenerally occur in the same tumor types, including cancers of the colon,lung and pancreas and melanoma, but are usually mutually exclusive. Thissuggests that activation of either Ras or Raf is sufficient for pathwayactivation and cancer progression.

Naturally occurring mutations of the B-Raf kinase that activate MAPKpathway signaling have been found in a large percentage of humanmelanomas (Davies (2002) supra) and thyroid cancers (Cohen et al J. Nat.Cancer Inst. (2003) 95(8) 625-627 and Kimura et al Cancer Res. (2003)63(7) 1454-1457), as well as at lower, but still significant,frequencies in the following: Barret's adenocarcinoma, billiary tractcarcinomas, breast cancer, cervical cancer, cholangiocarcinoma, centralnervous system tumors including primary CNS tumors such asglioblastomas, astrocytomas and ependymomas and secondary CNS tumors(i.e., metastases to the central nervous system of tumors originatingoutside of the central nervous system), colorectal cancer, includinglarge intestinal colon carcinoma, gastric cancer, carcinoma of the headand neck including squamous cell carcinoma of the head and neck,hematologic cancers including leukemias, acute myelogenous leukemia(AML), myelodysplastic syndromes and chronic myelogenous leukemia;Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemiaand multiple myeloma, hepatocellular carcinoma, lung cancer, includingsmall cell lung cancer and non-small cell lung cancer, ovarian cancer,endometrial cancer, pancreatic cancer, pituitary adenoma, prostatecancer, renal cancer, sarcoma, and skin cancers.

By virtue of the role played by the Raf family kinases in these cancersand exploratory studies with a range of preclinical and therapeuticagents, including one selectively targeted to inhibition of B-Raf kinaseactivity (King A. J., et al., (2006) Cancer Res. 66:11100-11105), it isgenerally accepted that inhibitors of one or more Raf family kinaseswill be useful for the treatment of such cancers or other conditionassociated with Raf kinase.

Mutation of B-Raf has also been implicated in other conditions,including cardio-facio cutaneous syndrome (Rodriguez-Viciana et alScience (2006) 311(5765) 1287-1290) and polycystic kidney disease (Nagaoet al Kidney Int. (2003) 63(2) 427-437).

Since tumor cells frequently become dependent to one or two keysignaling pathways for their survival (see, e.g. Jonkers et al., CancerCell. 6:535-538 (2004)), the Erk pathway represents a highly attractivetarget for drug intervention to treat cancer. Protein kinases in generalare considered desirable targets for drug therapy, as evidenced byrecent successes in targeting growth factor receptor and intracellulartyrosine kinases. Inhibitors of Mek have shown promise in clinicaltrials, however, there is ample evidence to indicate Mek-independent Rafsignaling that may also contribute to cancer progression (Wellbrock etal, Nat. Rev. Mol. Cell Biol. 11:875-885 (2004)). Therefore, targetingRaf kinases promises an alternative and complementary approach totreating tumors in which Ras or Raf genes are mutated.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of formula I:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein,

ring D is aryl or heteroaryl;

R is H, halo, or -A-B;

-   -   A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A),        NR_(A)C(O)NR_(A), or absent;    -   B is H, alkyl, alkoxy, cycloalkyl, or aryl, each of which is        optionally substituted;

R₁ is hydroxyl, alkyl, alkoxy, C(O)OR_(A), C(O)NR_(A)R_(B), orNR_(A)R_(B), each of which may be optionally substituted; or H or halo;

R′ is absent, or R and R′ together with the atoms to which each isattached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring,each of which is optionally substituted;

Z is NR_(A), O, NR_(A)C(O), C(O)NR_(A), CR₃R₄ or S(O)_(m);

R₃ is H or alkyl;

R₄ is H, alkyl, or absent;

or R₃ and R₄ together with the carbon to which each is attached formC(O);

ring E is monocyclic or bicyclic heteroaryl;

R_(z) is NR_(A)R₂;

-   -   R₂ is H, optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, C(O)R_(A),        C(O)OR_(A), C(O)NR_(A)R_(B), C(NR_(B))R_(A), or

C(NR_(B))OR_(A);

R₅ is H, halo, alkyl, alkoxy, or thioalkoxy;

R₆ is H, NR_(A)R_(B), or OR_(A);

-   -   each R_(A) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted;    -   each R_(B) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted;    -   or, for each occurrence of NR_(A)R_(B), R_(A) and R_(B) are        taken together with the nitrogen atom to which they are attached        to form a 3-7 membered heterocycloalkyl ring;

each m is independently 0, 1, or 2; and

each n is independently 0 or 1.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula I, or a pharmaceutically acceptableester, salt, or prodrug thereof, together with a pharmaceuticallyacceptable carrier.

In one aspect, the invention provides a method of inhibiting a b-rafkinase in a subject, comprising administering to the subject a compoundof formula I.

In another aspect, the invention provides a method of treating a diseaserelated to kinase modulation in a subject comprising administering tothe subject a compound or pharmaceutically acceptable salt of formula I;

wherein the kinase is selected from b-raf, Abl, Csf1R, EGFR, EphA8,FGFR1,2,3,4, FLT3, KIT, Lok, MAP4K1, MUSK, p38alpha, beta, PDGFRalpha,beta, Ret, Taok3, TNNI3K, Fes, Lyn SRPK1, STK36, TIE2, DDR1, EPHA2,ROIK1, RIOK3, NKF1LK, Src, Tak1, BLK, EphA4, EphB2, Fgr, FLT4, MAP4K2,ANKK1, Frk, Lck, Map4K5, Erbb4, Map4k4, MKNK2, Tec, Flt1, Hck, Tnk2,Txk, BTK, SLK, RiPK1, RIPK2, BIKE, CIT, CDKL2, DRAK, EphB1, JNK2, MLK1,MYLK2, TrkA,B,C, VEGFR2, IKKalpha, PTK2B, MAP4K3, Tie2, Fyn, Zak, DDR2,AurC, Lyn, Hpk1, Gck.

In another aspect, the invention provides a method of treating a diseaserelated to b-raf or b-raf mutation modulation in a subject comprisingadministering to the subject a compound or pharmaceutically acceptablesalt of formula I.

In other aspects, the invention provides a method of treating a diseaserelated to b-raf or b-raf mutation modulation in a subject comprising:administering to the subject identified as in need thereof a compound orpharmaceutically acceptable salt of formula I.

In another aspect, the invention provides a method of treating a diseaserelated to b-raf or b-raf mutation modulation in a subject, wherein thedisease is resistant to drug resistant mutations in b-raf, comprisingadministering to the subject a compound or pharmaceutically acceptablesalt of formula I.

In another aspect, the invention provides a method of treating cancer ina subject, wherein the cancer comprises b-raf activated tumors,comprising administering to the subject a compound or pharmaceuticallyacceptable salt of formula I.

In certain aspects, the invention provides a method of treating cancerin a subject, cancer comprises b-raf activated tumors, wherein thesubject is identified as being in need of b-raf inhibition for thetreatment of cancer, comprising administering to the subject a compoundor pharmaceutically acceptable salt of formula I.

In another aspect, the invention provides a use of a compound of theinvention for the preparation of a medicament for the treatment ofcancer.

In another aspect, the invention provides a kit comprising a compound orpharmaceutically acceptable salt of formula I capable of inhibitingb-raf or b-raf mutation activity; and instructions for use in treatingcancer.

DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1E: Table 1 shows compounds synthesized using a methoddescribed in Example 1.

FIGS. 2A to 2B: Table 2 shows compounds synthesized using a methoddescribed in Example 2.

FIGS. 3A to 3E: Table 3 shows compounds synthesized using a methoddescribed in Example 3.

FIGS. 4A to 4C: Table 4 shows compounds synthesized using a methoddescribed in Example 4.

FIGS. 5A to 5G: Table 5 shows compounds synthesized using a methoddescribed in Example 5.

FIGS. 6A to 6B: Table 6 shows compounds synthesized using a methoddescribed in Example 6.

FIGS. 7A to 7D: Table 7 shows compounds synthesized using a methoddescribed in Example 7.

FIG. 8: Table 8 shows compounds synthesized using a method described inExample 8.

FIGS. 9A to 9C: Table 9 shows compounds synthesized using a methoddescribed in Example 9.

FIGS. 10A to 10B: Table 10 shows compounds synthesized using a methoddescribed in Example 10.

FIGS. 11A to 11B: Table 11 shows compounds synthesized using a methoddescribed in Example 11.

FIGS. 12A to 12D: Table 12 shows compounds synthesized using a methoddescribed in Example 12.

FIG. 13: Table 13 shows compounds synthesized using a method describedin Example 13.

FIG. 14A shows the dose response IC50 calculation for XI-1 compared toreference Raf inhibitors; FIG. 14B shows the compound IC50 values onb-raf V600E transformed Ba/F3 cells.

FIGS. 15A to 15B: Summary of antiproliferative activity of XI-1 againsta variety of cancer cell lines.

FIG. 16A shows kinase targets of XI-1; FIG. 16B shows additional kinasetargets of XI-1.

FIGS. 17A to 17C: Additional targets of XI-1 determined using a chemicalproteomics approach.

FIGS. 18A to 18B: XI-1 can suppress B-RAF the ‘gatekeeper mutation’T529I, which confers resistance in other B-RAF inhibitors.

FIG. 19: Cellular proliferation IC₅₀ in micromolar of XI-1 against apanel of different cancer cell lines. IC₅₀s also shown for otherreference kinase inhibitors in micromolar.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “alkyl,” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals containing, in certain embodiments,between one and six, or one and eight carbon atoms, respectively.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl radicals; and examples of C₁-C₈ alkyl radicals include, but arenot limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,neopentyl, n-hexyl, heptyl, octyl radicals.

The term “alkenyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing, in certain embodiments, from twoto six, or two to eight carbon atoms having at least one carbon-carbondouble bond. The double bond may or may not be the point of attachmentto another group. Alkenyl groups include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl and the like.

The term “alkynyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing, in certain embodiments, from twoto six, or two to eight carbon atoms having at least one carbon-carbontriple bond. The alkynyl group may or may not be the point of attachmentto another group. Representative alkynyl groups include, but are notlimited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl,octynyl and the like.

The term “alkoxy” refers to an —O-alkyl radical.

The term “aryl,” as used herein, refers to a mono- or poly-cycliccarbocyclic ring system having one or more aromatic rings, fused ornon-fused, including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, idenyl and the like.

The term “aralkyl,” as used herein, refers to an alkyl residue attachedto an aryl ring. Examples include, but are not limited to, benzyl,phenethyl and the like.

The term “cycloalkyl” or “carbocyclic,” as used herein, denotes amonovalent group derived from a monocyclic or polycyclic saturated orpartially unsaturated carbocyclic ring compound. Examples ofC₃-C₈-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo[2.2.1] heptyl, and bicyclo[2.2.2]octyl. Also contemplated are a monovalent group derived from amonocyclic or polycyclic carbocyclic ring compound having at least onecarbon-carbon double bond by the removal of a single hydrogen atom.Examples of such groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

The term “heteroaryl,” as used herein, refers to a mono- or poly-cyclic(e.g., bi-, or tri-cyclic or more) fused or non-fused, radical or ringsystem having at least one aromatic ring, having from five to ten ringatoms of which one ring atoms is selected from S, O and N; zero, one ortwo ring atoms are additional heteroatoms independently selected from S,O and N; and the remaining ring atoms are carbon. Heteroaryl includes,but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.

The term “heteroaralkyl,” as used herein, refers to an alkyl residueattached to a heteroaryl ring. Examples include, but are not limited to,pyridinylmethyl, pyrimidinylethyl and the like.

The term “heterocycloalkyl,” as used herein, refers to a non-aromatic3-, 4-, 5-, 6- or 7-membered ring or a bi- or tri-cyclic group fused ofnon-fused system, where (i) each ring contains between one and threeheteroatoms independently selected from oxygen, sulfur and nitrogen,(ii) each 5-membered ring has 0 to 1 double bonds and each 6-memberedring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatomsmay optionally be oxidized, (iv) the nitrogen heteroatom may optionallybe quaternized, and (iv) any of the above rings may be fused to abenzene ring. Representative heterocycloalkyl groups include, but arenot limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl) where C₁-C₁₂ alkyl is as previously defined.

The terms “hal,” “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. The term “optionally substituted,” refers togroups that are substituted or unsubstituted by independent replacementof one, two, or three or more of the hydrogen atoms thereon withsubstituents including, but not limited to:

-alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,

—F, —Cl, —Br, —I,

—OH, protected hydroxy,

—NO₂, —CN,

—NH₂, protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,

—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,

—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl,

—CONH₂, —CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl,

—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,

—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂— C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl,

—C(NH)NH—C₁-C₁₂-alkyl, —C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH— heterocycloalkyl,

—S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl,—S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH— C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,

—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl,

—CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl,-heterocycloalkyl, —C₃-C₁₂-cycloalkyl, polyalkoxyalkyl, polyalkoxy,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “cancer” includes, but is not limited to, the followingcancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal; rectum, Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma, lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), myeloma, multiple myeloma, malignant giantcell tumor chordoma, osteochronfroma (osteocartilaginous exostoses),benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteomaand giant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma)), breast;Hematologic: blood (myeloid leukemia (acute and chronic), acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating disorders through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxyysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

Compounds of the Invention

In one aspect, the invention provides a compound of formula I:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

ring D is aryl or heteroaryl;

R is H, halo, or -A-B;

-   -   A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A),        NR_(A)C(O)NR_(A), or absent;    -   B is H, alkyl, alkoxy, cycloalkyl, or aryl, each of which is        optionally substituted;

R₁ is hydroxyl, alkyl, alkoxy, C(O)OR_(A), C(O)NR_(A)R_(B), orNR_(A)R_(B), each of which may be optionally substituted; or H or halo;

R′ is absent, or R and R′ together with the atoms to which each isattached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring,each of which is optionally substituted;

Z is NR_(A), O, NR_(A)C(O), C(O)NR_(A), CR₃R₄ or S(O)_(m);

R₃ is H or alkyl;

R₄ is H, alkyl, or absent;

or R₃ and R₄ together with the carbon to which each is attached formC(O);

ring E is monocyclic or bicyclic heteroaryl;

R_(z) is NR_(A)R₂;

-   -   R₂ is H, optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, C(O)R_(A),        C(O)OR_(A), C(O)NR_(A)R_(B), C(NR_(B))R_(A), or C(NR_(B))OR_(A);

R₅ is H, halo, alkyl, alkoxy, or thioalkoxy;

R₆ is H, NR_(A)R_(B), or OR_(A);

-   -   each R_(A) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted;    -   each R_(B) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted;    -   or, for each occurrence of NR_(A)R_(B), R_(A) and R_(B) are        taken together with the nitrogen atom to which they are attached        to form a 3-7 membered heterocycloalkyl ring;

each m is independently 0, 1, or 2; and

each n is independently 0 or 1.

In certain embodiments, ring D is selected from phenyl, naphthyl,tetrahydronaphthyl, indanyl, idenyl, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, pyrrolo pyridinyl, thiazolo pyridinyl, imidazolyl,thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl,furanyl, indazolyl, indolonyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzooxazolyl, and quinoxalinyl.

In a further embodiment, ring D is selected from phenyl, naphthyl,pyrazinyl, pyrimidinyl, pyrrolo pyridinyl, thiazolo pyridinyl,indazolyl, indolonyl, and quinolinyl.

In another embodiment, ring E is selected from phenyl, naphthyl,tetrahydronaphthyl, indanyl, idenyl, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiophenyl, furanyl, indazolyl, indolonyl, quinolinyl, isoquinolinyl,quinazolinyl, 1H-pyrrolo[2,3-b]pyridine, 9H-purine,7H-pyrrolo[2,3-d]pyrimidine, 1H-pyrazolo[3,4-d]pyrimidine, andquinoxalinyl.

In a further embodiment, ring E is selected from phenyl, naphthyl,pyridinyl, pyrazinyl, and pyrimidinyl.

In a first embodiment, the invention provides a compound of formula II:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

Z is NH or O;

R is H or -A-B;

-   -   A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), or        absent;    -   B is alkyl, alkoxy, or aryl, each of which is optionally        substituted;

R₁ is H, alkyl, alkoxy, or halo; each of which may be optionallysubstituted;

R₂ is H, C(O)R_(A), C(O)OR_(A), C(O)NR_(A)R_(B), C(NR_(B))R_(A), orC(NR_(B))OR_(A);

-   -   each R_(A) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted;    -   each R_(B) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted; and

m is 0, 1, or 2.

In certain embodiments, R₂ is H, C(O)R_(A), C(O)OR_(A), orC(O)NR_(A)R_(B).

In a further embodiment, each R_(A) is independently H, alkyl, orcycloalkyl, each of which may be optionally substituted; and R_(B) is H.

In other embodiments, R₂ is H,

In certain embodiments, R₁ is H, alkyl, alkoxy, or halo.

In a further embodiment, R₁ is H, methyl, methoxy, or chloro.

In other embodiments, R is H or -A-B; A is NR_(A)C(O), C(O), C(O)O,C(O)NR_(A), or absent; and B is alkyl, alkoxy, or aryl, each of which isoptionally substituted.

In a further embodiment, A is NHC(O), C(O)O, C(O)NH, or absent.

In a further embodiment, B is phenyl, methyl, or methoxy; each of whichis optionally substituted.

In other further embodiments, B is optionally substituted with alkyl,alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, or hydroxyl, each of which is optionally substituted.

In certain embodiments, R is selected from H, methyl, methoxy,

In a second embodiment, the invention provides a compound of formulaIII:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

ring D is aryl or heteroaryl;

R is H, halo, or -A-B;

-   -   A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), or        absent;    -   B is H, alkyl, cycloalkyl, or aryl, each of which is optionally        substituted;

R₁ is H, hydroxyl, alkyl, alkoxy, C(O)OR_(A), C(O)NR_(A)R_(B),NR_(A)R_(B), or halo; each of which may be optionally substituted;

R′ is absent, or R and R′ together with the atoms to which each isattached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring,each of which is optionally substituted;

R₂ is H, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocycloalkyl, C(O)R_(A), C(O)OR_(A),C(O)NR_(A)R_(B), C(NR_(B))R_(A), or C(NR_(B))OR_(A);

-   -   each R_(A) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted;    -   each R_(B) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted; and

m is 0, 1, or 2.

In certain embodiments, R₂ is H, optionally substituted aryl, oroptionally substituted heteroaryl.

In other embodiments, R₂ is H, phenyl, pyridyl, pyrimidinyl, each ofwhich is optionally substituted.

In a further embodiment, R₂ is H,

In various embodiments, ring D is phenyl, pyrrolo pyridine,benzothiazole, indazole, pyrazine, or indolinone.

In other embodiments, R₁ is H, hydroxyl, alkyl, NR_(A)R_(B), or halo;each of which may be optionally substituted.

In other embodiments, R is H, halo, or -A-B; A is NR_(A)C(O), O,S(O)_(m), C(O), C(O)O, C(O)NR_(A), or absent; and B is alkyl,cycloalkyl, or aryl, each of which is optionally substituted.

In various embodiments, A is NHC(O), C(O)O, C(O)NH, or absent.

In a further embodiment, B is H, alkyl, cycloalkyl, or aryl, each ofwhich is optionally substituted.

In another further embodiment, B is optionally substituted with alkyl,alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, halo, or hydroxyl, each of which is optionally substituted.

In other embodiments, R is H, methyl, Cl, F, COOH, C(O)NHCH₃,

In a third embodiment, the invention provides a compound of formula IV:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

R is H or -A-B;

-   -   A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), or        absent;    -   B is alkyl or aryl, each of which is optionally substituted;

R₁ is H, alkyl, alkoxy, or halo; each of which may be optionallysubstituted;

Z is NR_(A), O, or S(O)_(m);

R₃ is H or alkyl;

R₄ is H or alkyl;

or R₃ and R₄ together with the carbon to which each is attached formC(O);

R₅ is H, halo, alkoxy, or thioalkoxy, each R_(A) is independently H,alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each ofwhich may be optionally substituted; and

each m is independently 0, 1, or 2.

In one embodiment, Z is NR_(A) or O; R₃ is H; R₄ is H; or R₃ and R₄together with the carbon to which each is attached form C(O).

In a further embodiment, Z is NH or O.

In certain embodiments, R₅ is H, halo, alkoxy, or thioalkoxy.

In a further embodiment, R₅ is H, Cl, methoxy, or S(i-Pr).

In other embodiments, R₁ is H, alkyl, or alkoxy; each of which may beoptionally substituted.

In another embodiment, R is -A-B; A is NR_(A)C(O) or C(O)NR_(A); and Bis alkyl or aryl, each of which is optionally substituted.

In various embodiments, A is NHC(O) or C(O)NH.

In other embodiments, B is alkyl or aryl, each of which is optionallysubstituted.

In a further embodiment, B is optionally substituted with alkyl,alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, halo, or hydroxyl, each of which is optionally substituted.

In another embodiment, R is

In a fourth embodiment, the invention provides a compound of formula V:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

R is H or -A-B;

-   -   A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), or        absent;    -   B is alkyl or aryl, each of which is optionally substituted;

R₁ is H, alkyl, alkoxy, or halo; each of which may be optionallysubstituted;

R₅ is H, halo, alkoxy, or thioalkoxy,

-   -   each R_(A) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted; and

m is 0, 1, or 2.

In one embodiment, R₅ is halo or alkoxy.

In a further embodiment, R₅ is Cl or methoxy.

In other embodiments, R₁ is alkyl, which may be optionally substituted.

In certain embodiments, R is -A-B; A is NR_(A)C(O) or C(O)NR_(A); and Bis alkyl or aryl, each of which is optionally substituted.

In a further embodiment, A is NHC(O) or C(O)NH.

In a further embodiment, B is alkyl or aryl, each of which is optionallysubstituted.

In a further embodiment, B is optionally substituted with alkyl,alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, halo, or hydroxyl, each of which is optionally substituted.

In certain embodiments, R is

In a fifth embodiment, the invention provides a compound of formula VI:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

ring D is aryl or heteroaryl;

R is H, halo, or -A-B;

-   -   A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), or        absent;    -   B is alkyl, cycloalkyl, or aryl, each of which is optionally        substituted;

R₁ is H, hydroxyl, alkyl, alkoxy, C(O)OR_(A), C(O)NR_(A)R_(B),NR_(A)R_(B), or halo; each of which may be optionally substituted;

R₆ is H, NR_(A)R_(B), or OR_(A);

R₅ is H, halo, alkoxy, or thioalkoxy,

-   -   each R_(A) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted;    -   each R_(B) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted; and

m is 0, 1, or 2.

In one embodiment, R₆ is H or NR_(A)R_(B).

In certain embodiments, R_(A) is an optionally substituted aryl andR_(B) is H.

In other embodiments, R₅ is H or Cl.

In another embodiment, ring D is phenyl, naphthyl, indolonyl, orquinolinyl.

In a further embodiment, R₁ is H.

In another further embodiment, R is -A-B; A is NR_(A)C(O) or C(O)NR_(A);and B is alkyl or aryl, each of which is optionally substituted.

In a further embodiment, A is NHC(O) or C(O)NH.

In another further embodiment, B is alkyl or phenyl, each of which isoptionally substituted.

In a further embodiment, B is optionally substituted with alkyl,alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, halo, or hydroxyl, each of which is optionally substituted.

In certain embodiments, R is

In certain embodiments, the invention provides a compound of formulaVII:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein,

ring D is aryl;

A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), NR_(A)C(O)NR_(A),or absent;

B is H, alkyl, alkoxy, cycloalkyl, or aryl, each of which is optionallysubstituted;

Z is NR_(A), O, NR_(A)C(O), C(O)NR_(A), or S(O)_(m);

ring E is monocyclic or bicyclic heteroaryl;

R_(z) is NR_(A)R₂;

-   -   R₂ is H, optionally substituted aryl, optionally substituted        heteroaryl, optionally substituted heterocycloalkyl, C(O)R_(A),        C(O)OR_(A), C(O)NR_(A)R_(B), C(NR_(B))R_(A), or C(NR_(B))OR_(A);

R₅ is H, halo, alkyl, alkoxy, or thioalkoxy;

R₆ is H, NR_(A)R_(B), or OR_(A);

-   -   each R_(A) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted;    -   each R_(B) is independently H, alkyl, alkenyl, cycloalkyl,        heterocyclic, aryl or heteroaryl, each of which may be        optionally substituted; and each n is independently 0 or 1.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula I, or a pharmaceutically acceptableester, salt, or prodrug thereof, together with a pharmaceuticallyacceptable carrier.

Representative compounds of the invention include, but are not limitedto, the following compounds found in FIGS. 1A to 13 (and Tables 1-13)and the Examples below.

The invention also provides for a pharmaceutical composition comprisinga compound of formula I, or a pharmaceutically acceptable ester, salt,or prodrug thereof, together with a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method of method ofsynthesizing a compound of formula I.

The synthesis of the compounds of the invention can be found in theExamples below.

Another embodiment is a method of making a compound of any of theformulae herein using any one, or combination of, reactions delineatedherein. The method can include the use of one or more intermediates orchemical reagents delineated herein.

Another aspect is an isotopically labeled compound of any of theformulae delineated herein. Such compounds have one or more isotopeatoms which may or may not be radioactive (e.g., ³H, ²H, ¹⁴C, ¹³C, ³⁵S,³²P, ¹⁵I, and ¹³¹I) introduced into the compound. Such compounds areuseful for drug metabolism studies and diagnostics, as well astherapeutic applications.

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase.

Alternatively, the salt forms of the compounds of the invention can beprepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3.sup.rd edition, John Wiley and Sons,Inc., 1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

In addition, some of the compounds of this invention have one or moredouble bonds, or one or more asymmetric centers. Such compounds canoccur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double isomeric forms, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)-, or as(D)- or (L)- for amino acids. All such isomeric forms of these compoundsare expressly included in the present invention. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Thecompounds of this invention may also be represented in multipletautomeric forms, in such instances, the invention expressly includesall tautomeric forms of the compounds described herein (e.g., alkylationof a ring system may result in alkylation at multiple sites, theinvention expressly includes all such reaction products). When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion. All such isomeric forms of suchcompounds are expressly included in the present invention. All crystalforms of the compounds described herein are expressly included in thepresent invention.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent invention. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this invention may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in theart.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Methods of the Invention

In one aspect, the invention provides a method of inhibiting a b-rafkinase in a subject, comprising administering to the subject a compoundof formula I.

In one embodiment, the b-raf kinase is a mutation.

In another embodiment, the b-raf kinase mutation is V600E, T529I, orV600E/T529I.

In another aspect, the invention provides a method of treating a diseaserelated to kinase modulation in a subject comprising administering tothe subject a compound or pharmaceutically acceptable salt of formula I;

wherein the kinase is selected from b-raf, Abl, Csf1R, EGFR, EphA8,FGFR1,2,3,4, FLT3, KIT, Lok, MAP4K1, MUSK, p38alpha, beta, PDGFRalpha,beta, Ret, Taok3, TNNI3K, Fes, Lyn SRPK1, STK36, TIE2, DDR1, EPHA2,ROIK1, RIOK3, NKF1LK, Src, Tak1, BLK, EphA4, EphB2, Fgr, FLT4, MAP4K2,ANKK1, Frk, Lck, Map4K5, Erbb4, Map4k4, MKNK2, Tec, Flt1, Hck, Tnk2,Txk, BTK, SLK, RiPK1, RIPK2, BIKE, CIT, CDKL2, DRAK, EphB1, JNK2, MLK1,MYLK2, TrkA,B,C, VEGFR2, IKKalpha, PTK2B, MAP4K3, Tie2, Fyn, Zak, DDR2,AurC, Lyn, Hpk1, and Gck.

In one embodiment, the kinase is selected from b-raf b-raf, Abl, Csf1R,EGFR, EphA8, FGFR1,2,3,4, FLT3, KIT, Lok, MAP4K1, MUSK, p38alpha, beta,PDGFRalpha, beta, Ret, Taok3, TNNI3K, Fes, Lyn SRPK1, STK36, TIE2, DDR1,EPHA2, ROIK1, RIOK3, NKF1LK, Src, Tak1, BLK, EphA4, EphB2, Fgr, FLT4,MAP4K2, ANKK1, Frk, Lck, Map4K5, Erbb4, Map4k4, MKNK2, Tec, Flt1, Hck,Tnk2, Txk, BTK, SLK, RiPK1, RIPK2, BIKE, CIT, CDKL2, DRAK, EphB1, JNK2,MLK1, MYLK2, TrkA,B,C, VEGFR2, IKKalpha, PTK2B, MAP4K3, Tie2, Fyn, Zak,DDR2, AurC, Lyn, Hpk1, and Gck.

In another aspect, the invention provides a method of treating a diseaserelated to b-raf or b-raf mutation modulation in a subject comprisingadministering to the subject a compound or pharmaceutically acceptablesalt of formula I.

In other aspects, the invention provides a method of treating a diseaserelated to b-raf or b-raf mutation modulation in a subject comprising:administering to the subject identified as in need thereof a compound orpharmaceutically acceptable salt of formula I.

In various embodiments, the modulation is inhibition.

In other embodiments, the b-raf mutation is V600E, T529I, or V600E/T529I

In certain embodiments, the disease is cancer or a proliferationdisease.

In a further embodiment, the disease is melanoma, lung cancer, coloncancer, breast cancer, prostate cancer, liver cancer, pancreas cancer,brain cancer, kidney cancer, ovarian cancer, stomach cancer, skincancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer,glioma, glioblastoma, hepatocellular carcinoma, papillary renalcarcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas,myelomas, or solid tumors.

In certain embodiments, the subject is administered an additionaltherapeutic agent.

In a further embodiment, the compound and the additional therapeuticagent are administered simultaneously or sequentially.

In various embodiments, the additional therapeutic is a b-raf inhibitor.

In one embodiment, the additional therapeutic is a clinical b-rafinhibitor that directly targets the b-raf ATP site.

In a further embodiment, the additional therapeutic is sorafenib,Raf265, AZ628, PLX-4032, PLX-4720, gefitinib, erlotinib, lapatinib,XL-647, HKI-272, BIBW2992, AV-412, CI-1033, PF00299804, BMS 690514,cetuximab, panitumumab, or matuzumab.

In another aspect, the invention provides a method of treating a diseaserelated to b-raf or b-raf mutation modulation in a subject, wherein thedisease is resistant to drug resistant mutations in b-raf, comprisingadministering to the subject a compound or pharmaceutically acceptablesalt of formula I.

In certain embodiments, the b-raf mutation is V600E, T529I, orV600E/T529I.

In another aspect, the invention provides a method of treating cancer ina subject, wherein the cancer comprises b-raf activated tumors,comprising administering to the subject a compound or pharmaceuticallyacceptable salt of formula I.

In certain aspects, the invention provides a method of treating cancerin a subject, cancer comprises b-raf activated tumors, wherein thesubject is identified as being in need of b-raf inhibition for thetreatment of cancer, comprising administering to the subject a compoundor pharmaceutically acceptable salt of formula I.

In various embodiments, the disease is melanoma, lung cancer, coloncancer, breast cancer, prostate cancer, liver cancer, pancreas cancer,brain cancer, kidney cancer, ovarian cancer, stomach cancer, skincancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer,glioma, glioblastoma, hepatocellular carcinoma, papillary renalcarcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas,myelomas, or solid tumors.

In certain embodiments, the invention provides a method as describedabove wherein the subject is a human.

In another aspect, the invention provides a kit comprising a compound orpharmaceutically acceptable salt of formula I capable of inhibitingb-raf or b-raf mutation activity; and instructions for use in treatingcancer.

In certain aspects, the invention provides type II kinase inhibitorsthat target the mutant (V600E) b-raf pathway. Such compounds are weakdirect inhibitors of b-raf and predominantly target a number of kinasesupstream of b-raf. Thus, the compounds of the invention are b-rafpathway inhibitors.

In another embodiment, the present invention provides a method fortreating or lessening the severity of a kinase disease, condition, ordisorder where inhibition of a kinase is implicated in the treatment ofthe disease, wherein the kinase is selected from ABL1, ABL2, BRAF,CSF1R, EGFR, EPHA8, FGFR4, FLT3, KIT, LOK, MAP4K1, MUSK, p38-beta,PDGFRA, PDGFRB, RET, TAOK3, or TNNI3K.

In other embodiments, present invention provides a method for treatingor lessening the severity of a kinase disease, condition, or disorderwhere inhibition of a kinase is implicated in the treatment of thedisease, wherein the kinase is selected from FES, LYN, p38-alpha, SRPK1,STK36, TIE2, DDR1, EPHA2, RIOK1, RIOK3, SNF1LK, SRC, TAK1, BLK, EPHA4,EPHB2, FGR, FLT4, MAP4K2, ANKK1, FRK, LCK, MAP4K5, EGFR, ERBB4, MAP4K4,MKNK2, TEC, FLT1, HCK, TNK2, TXK, BTK, SLK, RIPK1, RIPK2, BIKE, CIT,CDKL2, DRAK1, EPHB1, JNK2, BRAF, MLK1, MYLK2, TRKB, VEGFR2, YES,IKK-alpha, PTK2B, MAP4K3, TIE1, FYN, FGFR1, ZAK, DDR2, RAF1, or AURKC.

In other embodiments, present invention provides a method for treatingor lessening the severity of a kinase disease, condition, or disorderwhere inhibition of a kinase is implicated in the treatment of thedisease, wherein the kinase is selected from LYN, CSK, ABL1/2, TAO1/3,HPK1, FGR, p38a, FES, FER, TAO2, KHS1/2, AurA/B/C, MAP3K2, PYK2, MPSK1,p38a, NEK9, PKD1/2, LOK, IRAK4, MST2, NEK9, PLK1, MST1, CK2a2, GSK3A,CDK7, AMPKa1/2, IRE1, AurA, MARK3, p38d/g, KSER, PIP5K2a, STLK5, MAP2K4,PITSLRE, CDK2, RSK1/2/3, PHKg2, PLK2, CDK10, Erk1/2, CaMK2g, NEK6/7,DYRK1B, CDK6, CDK5, CHK1, SYK, GSK3B, Wnk1/2/4, RPS6KC1, p38d, DMPK1,PKCa/b, SMG1, ROCK1/2, MAP3K5, CHED, BARK1/2, MST4, YSK1, CK1a, BRAF,PKR, PKN2, LKB1, or STLK5.

In another aspect, the present invention provides a method for treatingor lessening the severity of a kinase disease, condition, or disorderwhere inhibition of b-raf is implicated in the treatment of the disease.

As inhibitors of b-raf kinases, the compounds and compositions of thisinvention are particularly useful for treating or lessening the severityof a disease, condition, or disorder where b-raf is implicated in thedisease, condition, or disorder. In one aspect, the present inventionprovides a method for treating or lessening the severity of a disease,condition, or disorder where related to b-raf. In one embodiment, thedisease is related to a mutant b-raf such as V600E.

In another aspect, the present invention provides a method for treatingor lessening the severity of a kinase disease, condition, or disorderwhere inhibition of b-raf is implicated in the treatment of the disease.

In other aspects, the invention is directed towards provides a methodfor treating or lessening the severity of a b-raf related disease,condition, or disorder wherein b-raf mutations have provided forresistance to known drugs. In one embodiment, the mutation is T5291I.

In a further embodiment, the disease is melanoma, lung cancer, coloncancer, breast cancer, prostate cancer, liver cancer, pancreas cancer,brain cancer, kidney cancer, ovarian cancer, stomach cancer, skincancer, melanoma, leukemia, bone cancer, gastric cancer, breast cancer,pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma,papillary renal carcinoma, head and neck squamous cell carcinoma,leukemias, lymphomas, myelomas, solid tumors, colorectal cancer,epithelial call-derived neoplasia (epithelial carcinoma), basal cellcarcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouthcancer, esophageal cancer, small bowel cancer, stomach cancer, bladdercancer, cervical cancer, squamous cell and/or basal cell cancers,prostate cancer, renal cell carcinoma, or other known cancers thataffect epithelial cells throughout the body.

This invention further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subject compoundsmay be administered for the purpose of preventing said hyperplasias,dysplasias or pre-cancerous lesions from continuing to expand or frombecoming cancerous. Examples of pre-cancerous lesions may occur in skin,esophageal tissue, breast and cervical intra-epithelial tissue.

In other embodiments, the disease is inflammation, arthritis, rheumatoidarthritis, spondylarthropathies, gouty arthritis, osteoarthritis,juvenile arthritis, and other arthritic conditions, systemic lupuserthematosus (SLE), skin-related conditions, psoriasis, eczema, burns,dermatitis, neuroinflammation, allergy, pain, neuropathic pain, fever,pulmonary disorders, lung inflammation, adult respiratory distresssyndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonaryinflammatory disease, and chronic obstructive pulmonary disease (COPD),cardiovascular disease, arteriosclerosis, myocardial infarction(including post-myocardial infarction indications), thrombosis,congestive heart failure, cardiac reperfusion injury, as well ascomplications associated with hypertension and/or heart failure such asvascular organ damage, restenosis, cardiomyopathy, stroke includingischemic and hemorrhagic stroke, reperfusion injury, renal reperfusioninjury, ischemia including stroke and brain ischemia, and ischemiaresulting from cardiac/coronary bypass, neurodegenerative disorders,liver disease and nephritis, gastrointestinal conditions, inflammatorybowel disease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, ulcerative diseases, gastric ulcers, viral andbacterial infections, sepsis, septic shock, gram negative sepsis,malaria, meningitis, HIV infection, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, herpes virus, myalgias due to infection, influenza,autoimmune disease, graft vs. host reaction and allograft rejections,treatment of bone resorption diseases, osteoporosis, multiple sclerosis,cancer, angiogenesis including neoplasia, metastasis, central nervoussystem disorders, central nervous system disorders having aninflammatory or apoptotic component, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis, spinalcord injury, peripheral neuropathy, or Canine B-Cell Lymphoma.

In a further embodiment, the disease is inflammation, arthritis,rheumatoid arthritis, spondylarthropathies, gouty arthritis,osteoarthritis, juvenile arthritis, and other arthritic conditions,systemic lupus erthematosus (SLE), skin-related conditions, psoriasis,eczema, dermatitis, pain, pulmonary disorders, lung inflammation, adultrespiratory distress syndrome, pulmonary sarcoisosis, asthma, chronicpulmonary inflammatory disease, and chronic obstructive pulmonarydisease (COPD), cardiovascular disease, arteriosclerosis, myocardialinfarction (including post-myocardial infarction indications),congestive heart failure, cardiac reperfusion injury, inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome, leukemia,or lymphoma.

In some embodiments, said method is used to treat or prevent a conditionselected from autoimmune diseases, inflammatory diseases, proliferativeand hyperproliferative diseases, immunologically-mediated diseases, bonediseases, metabolic diseases, neurological and neurodegenerativediseases, cardiovascular diseases, hormone related diseases, allergies,asthma, and Alzheimer's disease. In other embodiments, said condition isselected from a proliferative disorder and a neurodegenerative disorder.

In certain embodiments, the disease is cancer. In a further embodiment,the disease is melanoma.

In certain embodiments, the invention provides a method of treatment ofany of the disorders described herein, wherein the subject is a human.

As inhibitors of b-raf kinases and b-raf mutations thereof, thecompounds and compositions of this invention are also useful inbiological samples. One aspect of the invention relates to inhibitingb-raf kinase activity in a biological sample, which method comprisescontacting said biological sample with a compound of the invention or acomposition comprising said compound. The term “biological sample”, asused herein, means an in vitro or an ex vivo sample, including, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of b-raf kinase activity in a biological sample is useful fora variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, and biological specimen storage.

Another aspect of this invention relates to the study of b-raf kinases,and mutations thereof, in biological and pathological phenomena; thestudy of intracellular signal transduction pathways mediated by suchprotein kinases; and the comparative evaluation of new protein kinaseinhibitors. Examples of such uses include, but are not limited to,biological assays such as enzyme assays and cell-based assays.

The activity of the compounds as b-raf kinase inhibitors may be assayedin vitro, in vivo or in a cell line. In vitro assays include assays thatdetermine inhibition of either the kinase activity or ATPase activity ofthe activated kinase. Alternate in vitro assays quantitate the abilityof the inhibitor to bind to the protein kinase and may be measuredeither by radiolabelling the inhibitor prior to binding, isolating theinhibitor/kinase complex and determining the amount of radiolabel bound,or by running a competition experiment where new inhibitors areincubated with the kinase bound to known radioligands.

In accordance with the foregoing, the present invention further providesa method for preventing or treating any of the diseases or disordersdescribed above in a subject in need of such treatment, which methodcomprises administering to said subject a therapeutically effectiveamount of a compound of the invention or a pharmaceutically acceptablesalt thereof. For any of the above uses, the required dosage will varydepending on the mode of administration, the particular condition to betreated and the effect desired.

Combination Therapy

Compounds of the invention can be administered in therapeuticallyeffective amounts in combination with one or more therapeutic agents(pharmaceutical combinations). For example, synergistic effects canoccur with other anti-proliferative, anti-cancer, immunomodulatory oranti-inflammatory substances. Where the compounds of the invention areadministered in conjunction with other therapies, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the condition beingtreated and so forth.

Combination therapy includes the administration of the subject compoundsin further combination with other biologically active ingredients (suchas, but not limited to, a second and different antineoplastic agent) andnon-drug therapies (such as, but not limited to, surgery or radiationtreatment). For instance, the compounds of the invention can be used incombination with other pharmaceutically active compounds, preferablycompounds that are able to enhance the effect of the compounds of theinvention. The compounds of the invention can be administeredsimultaneously (as a single preparation or separate preparation) orsequentially to the other drug therapy. In general, a combinationtherapy envisions administration of two or more drugs during a singlecycle or course of therapy.

In one aspect, the present invention provides a method for treating orlessening the severity of a kinase disease, condition, or disorder whereinhibition of b-raf is implicated in the treatment of the disease, andthe use of a b-raf inhibitor compound of the invention is used incombination with any current clinical b-raf inhibitor that directlytargets the b-raf ATP site. Such compounds include Sorafenib, Raf265,SB-590885, PLX4032, PLX4720, or AZ628, some of which are provided below:

In one aspect of the invention, the compounds may be administered incombination with one or more separate agents that modulate proteinkinases involved in various disease states. Examples of such kinases mayinclude, but are not limited to: serine/threonine specific kinases,receptor tyrosine specific kinases and non-receptor tyrosine specifickinases. Serine/threonine kinases include mitogen activated proteinkinases (MAPK), meiosis specific kinase (MEK), RAF and aurora kinase.Examples of receptor kinase families include epidermal growth factorreceptor (EGFR) (e.g. HER2/neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4,Xmrk, DER, Let23); fibroblast growth factor (FGF) receptor (e.g. FGF-R1,GFF-R2/BEK/CEK3, FGF-R3/CEK2, FGF-R4/TKF, KGF-R); hepatocytegrowth/scatter factor receptor (HGFR) (e.g., MET, RON, SEA, SEX);insulin receptor (e.g. IGFI-R); Eph (e.g. CEK5, CEK8, EBK, ECK, EEK,EHK-1, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); Axl (e.g. Mer/Nyk,Rse); RET; and platelet-derived growth factor receptor (PDGFR) (e.g.PDGFα-R, PDGβ-R, CSF1-R/FMS, SCF-R/C-KIT, VEGF-R/FLT, NEK/FLK1,FLT3/FLK2/STK-1). Non-receptor tyrosine kinase families include, but arenot limited to, BCR-ABL (e.g. p43.sup.abl, ARG); BTK (e.g. ITK/EMT,TEC); CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK and SYK.

In another aspect of the invention, the subject compounds may beadministered in combination with one or more agents that modulatenon-kinase biological targets or processes. Such targets include histonedeacetylases (HDAC), DNA methyltransferase (DNMT), heat shock proteins(e.g. HSP90), and proteosomes.

In a preferred embodiment, subject compounds may be combined withantineoplastic agents (e.g. small molecules, monoclonal antibodies,antisense RNA, and fusion proteins) that inhibit one or more biologicaltargets such as Zolinza, Tarceva, Iressa, Tykerb, Gleevec, Sutent,Sprycel, Nexavar, Sorafinib, CNF2024, RG108, BMS387032, Affinitak,Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322,Obatodax, ABT737 and AEE788. Such combinations may enhance therapeuticefficacy over efficacy achieved by any of the agents alone and mayprevent or delay the appearance of resistant mutational variants.

In certain preferred embodiments, the compounds of the invention areadministered in combination with a chemotherapeutic agent.Chemotherapeutic agents encompass a wide range of therapeutic treatmentsin the field of oncology. These agents are administered at variousstages of the disease for the purposes of shrinking tumors, destroyingremaining cancer cells left over after surgery, inducing remission,maintaining remission and/or alleviating symptoms relating to the canceror its treatment. Examples of such agents include, but are not limitedto, alkylating agents such as mustard gas derivatives (Mechlorethamine,cylophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimines(thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazinesand Triazines (Altretamine, Procarbazine, Dacarbazine and Temozolomide),Nitrosoureas (Carmustine, Lomustine and Streptozocin), Ifosfamide andmetal salts (Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloidssuch as Podophyllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxeland Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine andVinorelbine), and Camptothecan analogs (Irinotecan and Topotecan);anti-tumor antibiotics such as Chromomycins (Dactinomycin andPlicamycin), Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin,Mitoxantrone, Valrubicin and Idarubicin), and miscellaneous antibioticssuch as Mitomycin, Actinomycin and Bleomycin; anti-metabolites such asfolic acid antagonists (Methotrexate, Pemetrexed, Raltitrexed,Aminopterin), pyrimidine antagonists (5-Fluorouracil, Floxuridine,Cytarabine, Capecitabine, and Gemcitabine), purine antagonists(6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors(Cladribine, Fludarabine, Mercaptopurine, Clofarabine, Thioguanine,Nelarabine and Pentostatin); topoisomerase inhibitors such astopoisomerase I inhibitors (Irinotecan, topotecan) and topoisomerase IIinhibitors (Amsacrine, etoposide, etoposide phosphate, teniposide);monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab,Trastuzumab, Ibritumomab Tioxetan, Cetuximab, Panitumumab, Tositumomab,Bevacizumab); and miscellaneous anti-neoplastics such as ribonucleotidereductase inhibitors (Hydroxyurea); adrenocortical steroid inhibitor(Mitotane); enzymes (Asparaginase and Pegaspargase); anti-microtubuleagents (Estramustine); and retinoids (Bexarotene, Isotretinoin,Tretinoin (ATRA).

In certain preferred embodiments, the compounds of the invention areadministered in combination with a chemoprotective agent.Chemoprotective agents act to protect the body or minimize the sideeffects of chemotherapy. Examples of such agents include, but are notlimited to, amfostine, mesna, and dexrazoxane.

In one aspect of the invention, the subject compounds are administeredin combination with radiation therapy. Radiation is commonly deliveredinternally (implantation of radioactive material near cancer site) orexternally from a machine that employs photon (x-ray or gamma-ray) orparticle radiation. Where the combination therapy further comprisesradiation treatment, the radiation treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and radiation treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the radiation treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

It will be appreciated that compounds of the invention can be used incombination with an immunotherapeutic agent. One form of immunotherapyis the generation of an active systemic tumor-specific immune responseof host origin by administering a vaccine composition at a site distantfrom the tumor. Various types of vaccines have been proposed, includingisolated tumor-antigen vaccines and anti-idiotype vaccines. Anotherapproach is to use tumor cells from the subject to be treated, or aderivative of such cells (reviewed by Schirrmacher et al. (1995) J.Cancer Res. Clin. Oncol. 121:487). In U.S. Pat. No. 5,484,596, Hanna Jr.et al. claim a method for treating a resectable carcinoma to preventrecurrence or metastases, comprising surgically removing the tumor,dispersing the cells with collagenase, irradiating the cells, andvaccinating the patient with at least three consecutive doses of about10⁷ cells.

It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more adjunctivetherapeutic agents. Examples of suitable agents for adjunctive therapyinclude a 5HT₁ agonist, such as a triptan (e.g. sumatriptan ornaratriptan); an adenosine A1 agonist; an EP ligand; an NMDA modulator,such as a glycine antagonist; a sodium channel blocker (e.g.lamotrigine); a substance P antagonist (e.g. an NK₁ antagonist); acannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; aleukotriene receptor antagonist; a DMARD (e.g. methotrexate); gabapentinand related compounds; a tricyclic antidepressant (e.g. amitryptilline);a neurone stabilising antiepileptic drug; a mono-aminergic uptakeinhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; anitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOSinhibitor; an inhibitor of the release, or action, of tumour necrosisfactor a; an antibody therapy, such as a monoclonal antibody therapy; anantiviral agent, such as a nucleoside inhibitor (e.g. lamivudine) or animmune system modulator (e.g. interferon); an opioid analgesic; a localanaesthetic; a stimulant, including caffeine; an H₂-antagonist (e.g.ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g.aluminium or magnesium hydroxide; an antiflatulent (e.g. simethicone); adecongestant (e.g. phenylephrine, phenylpropanolamine, pseudoephedrine,oxymetazoline, epinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxyephedrine); an antitussive (e.g. codeine,hydrocodone, carmiphen, carbetapentane, or dextramethorphan); adiuretic; or a sedating or non-sedating antihistamine.

In certain embodiments, these compositions optionally further compriseone or more additional therapeutic agents. For example, chemotherapeuticagents or other antiproliferative agents may be combined with thecompounds of this invention to treat proliferative diseases and cancer.Examples of known chemotherapeutic agents include, but are not limitedto, Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

Other examples of agents the compounds of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept18 and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-I RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and antiparkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,antileukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula I, or a pharmaceutically acceptableester, salt, or prodrug thereof, together with a pharmaceuticallyacceptable carrier.

Compounds of the invention can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present invention in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present invention witha carrier. A carrier can include absorbable pharmacologically acceptablesolvents to assist passage through the skin of the host. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin. Matrixtransdermal formulations may also be used. Suitable formulations fortopical application, e.g., to the skin and eyes, are preferably aqueoussolutions, ointments, creams or gels well-known in the art. Such maycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Thepharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention,disorders are treated or prevented in a subject, such as a human orother animal, by administering to the subject a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired result. The term“therapeutically effective amount” of a compound of the invention, asused herein, means a sufficient amount of the compound so as to decreasethe symptoms of a disorder in a subject. As is well understood in themedical arts a therapeutically effective amount of a compound of thisinvention will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

In certain embodiments, a therapeutic amount or dose of the compounds ofthe present invention may range from about 0.1 mg/Kg to about 500 mg/Kg,alternatively from about 1 to about 50 mg/Kg. In general, treatmentregimens according to the present invention comprise administration to apatient in need of such treatment from about 10 mg to about 1000 mg ofthe compound(s) of this invention per day in single or multiple doses.Therapeutic amounts or doses will also vary depending on route ofadministration, as well as the possibility of co-usage with otheragents.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The invention also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of the invention and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of the invention and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes, oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate, agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The compounds of theinvention may be formulated into pharmaceutical compositions foradministration to animals or humans.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not to limit the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1N-(3-((5-aminopyrazin-2-yl)methylamino)-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

A. tert-butyl 5-methylpyrazin-2-ylcarbamate

To a solution of 5-methylpyrazine-2-carboxylic acid (500 mg, 3.62 mmol)in toluene (12 mL) were added DPPA (0.85 mL, 3.98 mmol), TEA (1.01 mL,7.24 mmol) and tert-butanol (3.4 mL, 36.2 mmol). The reaction mixturewas refluxed for 6 hours after which, it was partitioned between ethylacetate and water. The organic layer was separated and the aqueous layerwas extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over MgSO₄, celite filtered and concentratedunder reduced pressure. The crude product was purified by flashchromatography using (10% Ethyl acetate/Hexane) as a solvent to affordtitle compound (530 mg, 70% yield). ¹H NMR (600 MHz, CDCl₃) δ 9.15 (s,1H), 8.08 (s, 1H), 7.61 (s, 1H), 2.50 (s, 3H), 1.55 (s, 9H). MS m/z: 210[M+1].

B. tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate

To a solution tert-butyl 5-methylpyrazin-2-ylcarbamate (500 mg, 2.39mmol) in CCl₄ (8.0 mL) were added NBS (446 mg, 2.51 mmol) and AIBN (117mg, 0.72 mmol). The reaction mixture was stirred for 4 hours at 80° C.after which, it was partitioned between CH₂Cl₂ and water. The organiclayer was separated and the aqueous layer was extracted with CH₂Cl₂. Thecombined organic extracts were washed with brine, dried over MgSO₄,celite filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography using (10% Ethylacetate/Hexane) as a solvent to afford title compound (520 mg, 75%yield). ¹H NMR (600 MHz, CDCl₃) δ 9.29 (s, 1H), 8.95 (s, 1H), 8.37 (s,1H), 4.38 (s, 2H), 1.57 (s, 9H). MS m/z: 288 [M+1].

C. tert-butyl5-((5-(4-(4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenylamino)methyl)pyrazin-2-ylcarbamate

To a solutionN-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide(70 mg, 0.17 mmol) in DMF (0.5 mL) were added K₂CO₃ (69 mg, 0.50 mmol)and tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (48 mg, 0.17 mmol).The reaction mixture was stirred for 8 hours at room temperature afterwhich, it was partitioned between ethyl acetate and water. The organiclayer was separated and the aqueous layer was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover MgSO₄, filtered and concentrated. The crude product was purified byflash chromatography using (5% MeOH/CH₂Cl₂) as a solvent to afford titlecompound (50 mg, 47% yield). MS m/z: 628 [M+1].

D.N-(3-((5-aminopyrazin-2-yl)methylamino)-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

To a solution tert-butyl5-((5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenylamino)methyl)pyrazin-2-ylcarbamate(30 mg, 0.05 mmol) in CH₂Cl₂ (0.3 ml) was added TFA (18 μL, 0.24 mmol).The reaction mixture was stirred for 4 hours at room temperature afterwhich, it was concentrated under reduced pressure. The crude product waspurified by Prep HPLC and acetonitrile was removed under reducedpressure. The remained water was freeze-dried to afford TFA salt formedtitle compound (22 mg, 74% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 10.22 (s,1H), 8.17 (d, J=2.4 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.85 (s, 1H), 7.82(d, J=1.2 Hz, 1H), 7.65 (s, J=9.0 Hz, 1H), 7.14 (dd, J=1.8, 7.8 Hz, 2H),7.03 (d, J=1.8 Hz, 1H), 6.23 (s, 2H), 5.64 (t, J=6.0 Hz, 1H), 4.32 (d,J=5.4 Hz, 2H), 3.6 (brs, 2H), 3.40-3.25 (brs, 10H), 2.18 (s, 3H), 1.15(t, J=7.2 Hz, 3H). MS m/z: 528 [M+1].

Additional compounds made by the synthetic route of Example 1 are foundin FIGS. 1A to 1E.

Example 2 3-((5-aminopyrazin-2-yl)methylamino)-N,4-dimethylbenzamide

A. Methyl3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoate

Methyl3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoate(650 mg, 57% yield) was prepared as described for Example 1-C startingfrom methyl 3-amino-4-methylbenzoate (500 mg, 3.03 mmol). ¹H NMR (600MHz, CDCl₃) δ 9.26 (s, 1H), 8.25 (s, 1H), 7.52 (s, 1H), 7.38 (d, J=7.2Hz, 1H), 7.29 (s, 1H), 7.14 (d, J=7.2 Hz, 1H), 4.52 (s, 2H), 3.88 (s,3H), 2.26 (s, 3H), 1.55 (s, 9H). MS m/z: 373 [M+1].

B.3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoicacid

Methyl3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoate(600 mg, 1.61 mmol) in THF (2 mL) and MeOH (2 mL) was added LiOH.H₂O(338 mg, 8.06 mmol) in water (2 mL). The reaction mixture was stirredfor overnight at room temperature. The organic solvent was removed underreduced pressure and water (4 mL) was added to the reaction mixture. Toa reaction mixture was added 1N HCl solution to produce solid. The solidproduct was filtered and dried with nitrogen gas flow. The title product(460 mg, 79% yield) was used next reaction without further purification.MS m/z: 359 [M+1].

C. tert-butyl5-((2-methyl-5-(methylcarbamoyl)phenylamino)methyl)pyrazin-2-ylcarbamate

To a solution of3-((5-(tert-butoxycarbonylamino)pyrazin-2-yl)methylamino)-4-methylbenzoicacid (30 mg, 0.08 mmol) in DMF (1 mL) were added HATU (95 mg, 0.25mmol), DIEA (74 L, 0.42 mmol) and methylamine hydrochloride (9 mg, 0.13mmol). The reaction mixture was stirred for overnight at roomtemperature after which, it was partitioned between ethyl acetate andwater. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over MgSO₄, celite filtered and concentrated underreduced pressure. The crude product (29 mg, 93% yield) was used withoutfurther purification. MS m/z: 372 [M+1].

D. 3-((5-aminopyrazin-2-yl)methylamino)-N,4-dimethylbenzamide

3-((5-aminopyrazin-2-yl)methylamino)-N,4-dimethylbenzamide (21 mg, 70%yield) was prepared as described for Example 1-D starting fromtert-butyl 5-((2-methyl-5-(methylcarbamoyl)phenylamino)methyl)pyrazin-2-ylcarbamate (29 mg, 0.08 mmol). ¹H NMR (600 MHz, DMSO-d₆) δ8.10 (s, 1H), 7.81 (s, 2H), 7.01-6.90 (m, 3H), 6.21 (s, 2H), 5.40 (s,1H), 4.29 (s, 2H), 2.71 (s, 3H), 2.14 (s, 3H). MS m/z: 272 [M+1].

Additional compounds made by the synthetic route of Example 2 are foundin FIGS. 2A to 2B.

Example 3N-(3-((5-acetamidopyrazin-2-yl)methylamino)-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

A. 5-methylpyrazin-2-amine

To a solution tert-butyl 5-methylpyrazin-2-ylcarbamate (1.5 g, 7.17mmol) in CH₂Cl₂ (20 ml) was added TFA (2.6 mL, 35.86 mmol). The reactionmixture was stirred for 4 hours at room temperature after which, it wasconcentrated under reduced pressure. The reaction mixture was dilutedwith CH₂Cl₂ and neutralized with sat.NaHCO₃ solution. The organic layerwas separated and the aqueous layer was extracted with CH₂Cl₂. Thecombined organic extracts were washed with brine, dried over MgSO₄,celite filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography using (30% to 50% Ethylacetate/Hexane) as a solvent to afford title compound (580 mg, 74%yield). MS m/z: 110 [M+1].

B. N-(5-methylpyrazin-2-yl)acetamide

To a solution of 5-methylpyrazin-2-amine (300 mg, 2.75 mmol) in driedTHF (9 mL) were added acetyl chloride (0.21 mL, 2.89 mmol) and TEA (0.75mL, 5.50 mmol). The reaction mixture was stirred for 3 hours afterwhich, it was partitioned between ethyl acetate and water. The organiclayer was separated and the aqueous layer was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover MgSO₄, celite filtered and concentrated under reduced pressure. Thecrude product was purified by flash chromatography using (10% to 30%Ethyl acetate/Hexane) as a solvent to afford title compound (360 mg, 86%yield). MS m/z: 152 [M+1].

C. N-(5-(bromomethyl)pyrazin-2-yl)acetamide

N-(5-(bromomethyl)pyrazin-2-yl)acetamide (420 mg, 51% yield) wasprepared as described for Example 1-B starting fromN-(5-methylpyrazin-2-yl)acetamide (330 mg, 2.18 mmol). MS m/z: 231[M+1].

D.N-(3-((5-acetamidopyrazin-2-yl)methylamino)-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

To a solutionN-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide(50 mg, 0.12 mmol) in acetonitrile (0.5 mL) were added K₂CO₃ (49 mg,0.36 mmol) and N-(5-(bromomethyl)pyrazin-2-yl)acetamide (44 mg, 0.12mmol). The reaction mixture was filtered with celite and concentratedunder reduced pressure. The crude product was purified by Prep HPLC andacetonitrile was removed under reduced pressure. The remained water wasfreeze-dried to afford TFA salt formed title compound (40 mg, 49%yield). ¹H NMR (600 MHz, CD₃OD) δ 9.49 (d, J=1.2 Hz, 1H), 8.53 (d, J=1.2Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.94 (dd, J=1.8, 8.4 Hz, 1H), 7.74 (d,J=8.4 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.17 (dd, J=1.8, 7.8 Hz, 1H),7.12 (d, J=7.8 Hz, 1H), 4.72 (s, 2H), 3.84 (s, 2H), 3.68-3.64 (m, 2H),3.55-3.46 (m, 4H), 3.02-2.99 (m, 2H), 2.90-2.87 (m, 2H), 2.21 (s, 6H),1.49 (t, 7.2 Hz, 3H). MS m/z: 570 [M+1].

Additional compounds made by the synthetic route of Example 3 are foundin FIGS. 3A to 3E.

Example 4(E)-N-(3-(2-(5-aminopyrazin-2-yl)vinyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

A. Ethyl2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)benzoate

To a solution of ethyl 5-amino-2-methylbenzoate (500 mg, 2.79 mmol) andTEA (0.78 mL, 5.58 mmol) in dried THF (9 mL) was added4-(chloromethyl)-3-(trifluoromethyl)benzoyl chloride (714 mg, 2.79mmol). The reaction mixture was stirred for 5 hours at room temperatureafter which, it was concentrated under reduced pressure. To a solutionof the reaction mixture in acetonitrile (10 mL) were added methylpiperazine (558 mg, 5.58 mmol) and K₂CO₃ (1.1 g, 8.38 mmol). Thereaction mixture was stirred for 8 hours at room temperature. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The combined organic extracts were washed with brine,dried over MgSO₄, celite filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography using(3% to 7% Methanol/CH2Cl2) as a solvent to afford title compound (820mg, 63% yield). MS m/z: 464 [M+1].

B.N-(3-(hydroxymethyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

To a solution Ethyl2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)benzoate(300 mg, 0.65 mmol) in dried THF (2.2 mL) was added Lithium aluminiumhydride 2.0M THF solution (0.48 mL, 0.98 mmol) at 0° C. The reactionmixture was stirred for 2 hours at room temperature. When the reactionwas completed, the reaction mixture was diluted with ethyl ether (2.0mL) and added water very slowly to decompose the excess of the reagent.To a reaction mixture was added MgSO₄, celite filtered and concentratedunder reduced pressure. The title compound (230 mg, 84% yield) was usednext step without further purification. MS m/z: 422 [M+1].

C.N-(3-formyl-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

To a stirred solution ofN-(3-(hydroxymethyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide(200 mg, 0.47 mmol) in CH₂Cl₂ (2 mL) was added freshly dried 4 Å MS andNMO (83 mg, 0.71 mmol). The mixture was stirred for 10 min before TPAP(17 mg, 0.05 mmol) was added, and the resulting reaction mixture wasstirred 12 hours at room temperature. The reaction mixture was filteredthrough celite, concentrated under reduced pressure, and purified byflash column chromatography (3% to 7% MeOH/CH₂Cl₂) to afford titleproduct (175 g, 88% yield). MS m/z: 420 [M+1].

D. tert-butyl 5-((diethoxyphosphoryl)methyl)pyrazin-2-ylcarbamate

tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (2.5 g, 8.71 mmol) andtriethylphosphite (1.8 ml, 10.45 mmol) were placed in a 25 mL roundbottom flask. A distillation apparatus was attached to collect thepoisonous ethyl bromide formed during the reaction. The reaction mixturewas heated to 140° C. for 30 minutes and then cooled to roomtemperature. The reaction mixture was purified by flash columnchromatography (10% to 30% Ethyl acetate/Hexane) to afford title product(1.8 g, 60% yield). ¹H NMR (600 MHz, CDCl₃) δ 9.19 (s, 1H), 8.22 (t,J=1.8 Hz, 1H), 7.37 (s, 1H), 4.12-4.07 (m, 4H), 3.38 (s, 1H), 3.34 (s,1H), 1.54 (s, 9H), 1.29 (t, J=7.2 Hz, 6H). MS m/z: 346 [M+1].

E. (E)-tert-butyl5-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)styryl)pyrazin-2-ylcarbamate

tert-butyl 5-((diethoxyphosphoryl)methyl)pyrazin-2-ylcarbamate (35 mg,0.10 mmol) in dried DMF (0.5 mL) was added NaH (5 mg, 0.12 mmol) at 0°C. After 20 minutes, a solutionN-(3-formyl-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide(44 mg, 0.10 mmol) in dried DMF (0.5 mL) was added slowly into thereaction mixture. The reaction mixture was stirred overnight at roomtemperature and quenched by adding water. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic extracts were washed with brine, dried over MgSO₄,celite filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography using (3% to 7%MeOH/CH₂Cl₂) as a solvent to afford title compound (40 mg, 64% yield).MS m/z: 611 [M+1].

F.(E)-N-(3-(2-(5-aminopyrazin-2-yl)vinyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

(E)-N-(3-(2-(5-aminopyrazin-2-yl)vinyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide(25 mg, 81% yield) was prepared as described for Example 1-D startingfrom (E)-tert-butyl5-(2-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)styryl)pyrazin-2-ylcarbamate(30 mg, 0.05 mmol). MS m/z: 511 [M+1].

Additional compounds made by the synthetic route of Example 4 are foundin FIGS. 4A to 4C.

Example 5(E)-3-(2-(5-(4-(piperazin-1-ylsulfonyl)phenylamino)pyrazin-2-yl)vinyl)phenol

A. 5-vinylpyrazin-2-amine

To a mixture of 5-bromopyrazin-2-amine (1.0 g, 5.78 mmol) andvinyltri-n-butyltin (2.01 g, 6.36 mmol) in DMF (19 mL) were added LiCl(269 mg, 6.36 mmol) and DIEA (1.1 mL, 6.36 mmol). After degassing for 20minutes, Pd(PPh₃)₄ (400 mg, 0.35 mmol) was added to the reactionmixture. And then the mixture was refluxed for 4 hours under Aratmosphere. The reaction mixture was cooled to room temperature andstirred with a 10% aqueous solution of potassium fluoride for 1 hour.The resulting solution was filtered through a pad of celite and washedwith ethyl acetated. The aqueous layer was separated and extracted withethyl acetate. The combined organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The crude product was purified byflash column chromatography (30% to 50% Ethyl acetate/Hexane) to affordtitle product (540 mg, 77% yield). MS m/z: 122 [M+1].

B. tert-butyl4-(4-(5-vinylpyrazin-2-ylamino)phenylsulfonyl)piperazine-1-carboxylate

To a solution of 5-vinylpyrazin-2-amine (150 mg, 1.24 mmol) in 2-buOH (4mL) were added K₂CO₃ (512 mg, 3.71 mmol), and tert-butyl4-(4-aminophenylsulfonyl)piperazine-1-carboxylate (421 mg, 1.24 mmol).The reaction mixture was degassed for 10 minutes. To a mixture wereadded Pd₂(dba)₃ (76 mg, 0.07 mmol) and X-phos (53 mg, 0.11 mmol). Thereaction mixture was heated to 100° C. for 6 hours after which, it wasfiltered with a pad of celite and partitioned between ethyl acetate andwater. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over MgSO₄, celite filtered and concentrated underreduced pressure. The crude product was purified by flash chromatographyusing (20% to 30% Ethyl acetate/Hexane) as a solvent to afford titlecompound (360 mg, 65% yield). MS m/z: 446 [M+1].

C. (E)-tert-butyl4-(4-(5-(3-hydroxystyryl)pyrazin-2-ylamino)phenylsulfonyl)piperazine-1-carboxylate

A mixture of tert-butyl4-(4-(5-vinylpyrazin-2-ylamino)phenylsulfonyl)piperazine-1-carboxylate(40 mg, 0.09 mmol), 3-iodophenol (19 mg, 0.09 mmol), Pd(OAc)₂ (1.2 mg,0.005 mmol), tri-p-tolylphosphine (2.5 mg, 0.008 mmol), and DIEA (31 μL,0.18 mmol) in DMF (3 ml) was heated at 120° C. for 18 h after which, itwas filtered with a pad of celite and partitioned between ethyl acetateand water. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were washedwith brine, dried over MgSO₄, celite filtered and concentrated underreduced pressure. The crude product was purified by flash chromatographyusing (20% to 40% Ethyl acetate/Hexane) as a solvent to afford titlecompound (38 mg, 78% yield). MS m/z: 538 [M+1].

D.(E)-3-(2-(5-(4-(piperazin-1-ylsulfonyl)phenylamino)pyrazin-2-yl)vinyl)phenol

(E)-3-(2-(5-(4-(piperazin-1-ylsulfonyl)phenylamino)pyrazin-2-yl)vinyl)phenol(26 mg, 84% yield) was prepared as described for Example 1-D startingfrom (E)-tert-butyl4-(4-(5-(3-hydroxystyryl)pyrazin-2-ylamino)phenylsulfonyl)piperazine-1-carboxylate(30 mg, 0.06 mmol). MS m/z: 438 [M+1].

Additional compounds made by the synthetic route of Example 5 are foundin FIGS. 5A to 5G.

Example 64-chloro-N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

A. 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

To a solution 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg,2.78 mmol) in MC (9 mL) were added TsCl (556 mg, 2.91 mmol) and DMAP(509 mg, 4.17 mmol). The reaction mixture stirred for 8 hours at roomtemperature. The produced precipitated was filtered, washed with waterand dried with nitrogen gas flow. The title product (810 mg, 87% yield)was used without further purification. MS m/z: 335 [M+1].

B. 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid

To a stirred solution of NaH₂PO₄.2H₂O (513 mg, 3.3 mmol) in water (3ml), was added a solution of4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 1.50mmol) in acetone (6 ml) at 0° C. A solution of NaClO₂ (541 mg, 5.98mmol) in water (3 ml) was added to the reaction mixture at 0° C. and thereaction mixture was warmed to room temperature spontaneously. After 2hours, 1N HCl solution was added to reach pH=5. The produced solid wasfiltered and dried with nitrogen gas flow. The title product (440 mg,84% yield) was used next reaction without further purification. MS m/z:351 [M+1].

C.4-chloro-N-(5-(4((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

To a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylicacid (50 mg, 0.14 mmol) in DMF (1 mL) were added HATU (162 mg, 0.43mmol), DIEA (0.12 mL, 0.71 mmol) andN-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide(60 mg, 0.14 mmol). The reaction mixture was stirred for overnight atroom temperature after which, it was poured to water and the producedsolid was filtered. The crude solid was dried with nitrogen gas flow.The title compound (85 mg, 0.11 mmol) was used next reaction withoutfurther purification. MS m/z: 753 [M+1].

D.4-chloro-N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

To a solution of4-chloro-N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide(40 mg, 0.053 mmol) in dioxane (1 mL) was added NaOt-Bu (25 mg, 0.27mmol). The reaction mixture was stirred for 6 hours at 50° C. afterwhich, it was filtered with a pad of celite and partitioned betweenethyl acetate and water. The organic layer was separated and the aqueouslayer was extracted with ethyl acetate. The combined organic extractswere washed with brine, dried over MgSO₄, celite filtered andconcentrated under reduced pressure. The crude product was purified byPrep HPLC and acetonitrile was removed under reduced pressure. Theremained water was freeze-dried to afford TFA salt formed title compound(29 mg, 76% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 11.89 (s, 1H), 10.21 (s,1H), 9.33 (brs, 1H), 8.13 (s, 1H), 8.10 (s, 1H), 7.96 (d, J=7.8 Hz, 1H),7.60 (d, J=8.4 Hz, 1H), 7.50 (t, J=3.0 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H),7.10 (d, J=7.8 Hz, 1H), 6.98 (s, 1H), 6.43 (s, 1H), 4.55 (s, 2H),3.65-3.55 (m, 2H), 3.10-3.02 (m, 2H), 2.95-2.80 (m, 4H), 2.35-2.30 (m,2H), 2.17 (s, 3H), 1.14 (t, J=7.2 Hz, 3H). MS m/z: 599 [M+1].

Additional compounds made by the synthetic route of Example 6 are foundin FIGS. 6A to 6B.

Example 73-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (30mg, 0.17 mmol) in MeOH (1 mL) were added NaBH₃CN (52 mg, 0.83 mmol) andAcOH (29 μL, 0.50 mmol). The reaction mixture was stirred overnight atroom temperature. The organic solvent was removed under reducedpressure. The reaction mixture was neutralized with sat. NaHCO3 and theaqueous layer was extracted with ethyl acetate. The organic extractswere washed with brine, dried over MgSO₄, celite filtered andconcentrated under reduced pressure. The crude product was purified byPrep HPLC and acetonitrile was removed under reduced pressure. Theremained water was freeze-dried to afford TFA salt formed title compound(42 mg, 44% yield). ¹H NMR (600 MHz, DMSO-d₆) δ 11.91 (s, 1H), 10.25 (s,1H), 8.18 (d, J=12.0 Hz, 2H), 7.97 (d, J=7.8 Hz, 1H), 7.52-7.50 (m, 2H),7.36 (d, J=6.6 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H),7.04 (s, 1H), 6.47 (s, 1H), 4.60 (d, J=4.8 Hz, 2H), 3.15 (d, J=4.2 Hz,1H), 2.22 (s, 3H). MS m/z: 459 [M+1].

Additional compounds made by the synthetic route of Example 7 are foundin FIGS. 7A to 7D.

Example 8N-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

To a solutionN-(3-((4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide(10 mg, 0.017 mmol) in EtOH (1.0 mL) was added 10% Pd/C (2 mg). Aftertwo vacuum/H₂ cycles to replace air inside the reaction flask withhydrogen balloon, the reaction mixture was stirred at room temperaturefor 36 hours. The reaction mixture was filtered with a pad of celite andconcentrated under reduced pressure. The crude product was purified byPrep HPLC and acetonitrile was removed under reduced pressure. Theremained water was freeze-dried to afford TFA salt formed title compound(4 mg, 35% yield). MS m/z: 537 [M+1].

Additional compounds made by the synthetic route of Example 8 are foundin FIG. 8.

Example 94-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(methylphenyl)-3-(trifluoromethyl)benzamide

A.4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500mg, 2.78 mmol) in THF (9 mL) was added NaH (136 mg, 3.42 mmol) at 0° C.After 10 minutes, SEMCl (0.59 mL. 3.33 mmol) was added slowly to thereaction mixture at 0° C. The reaction mixture was warmed to roomtemperature and stirred for 2 hours after which, it was partitionedbetween ethyl acetate and water. The organic layer was separated and theaqueous layer was extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over MgSO₄, celite filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography using (5% to 20% Ethyl acetate/Hexane) as a solventto afford title compound (810 mg, 94% yield). ¹H NMR (600 MHz, CDCl₃) δ10.62 (s, 1H), 8.90 (s, 1H), 7.52 (d, J=3.6 Hz, 1H), 6.84 (d, J=4.2 Hz,1H), 5.76 (s, 2H), 3.60 (t, J=8.4 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0 (s,9H).

B.4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

Na (370 mg, 16.12 mmol) was dissolved in MeOH (5 mL) and4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(500 mg, 1.61 mmol) was added to the sodium methoxide solution. Thereaction mixture was stirred for 8 hours for 60° C. The reaction mixturewas quenched with water and the organic solvent was removed underreduced pressure. The resulting mixture was partitioned between ethylacetate and water. The organic layer was separated and the aqueous layerwas extracted with ethyl acetate. The combined organic extracts werewashed with brine, dried over MgSO₄, celite filtered and concentratedunder reduced pressure. The crude product was purified by flashchromatography using (5% to 20% Ethyl acetate/Hexane) as a solvent toafford title compound (380 mg, 77% yield). ¹H NMR (600 MHz, CDCl₃) δ10.51 (s, 1H), 8.74 (s, 1H), 7.36 (d, J=3.6 Hz, 1H), 6.90 (d, J=4.2 Hz,1H), 5.72 (s, 2H), 4.48 (s, 3H), 3.60 (t, J=7.8 Hz, 2H), 0.97 (t, J=8.4Hz, 2H), 0 (s, 9H). MS m/z: 307 [M+1].

C.4-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide

To a solution of4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(30 mg, 0.10 mmol) in dioxane (1 mL) were added NaBH(OAc)₃ (103 mg, 0.83mmol) and AcOH (6 μL, 0.10 mmol). The reaction mixture was stirredovernight at room temperature. The reaction mixture was neutralized withsat. NaHCO₃ and the aqueous layer was extracted with ethyl acetate. Theorganic extracts were washed with brine, dried over MgSO₄, celitefiltered and concentrated under reduced pressure. The crude product waspurified by flash chromatography using (1% to 7% MeOH/CH₂Cl₂) as asolvent to afford title compound (43 mg, 61% yield). MS m/z: 711 [M+1].

D.4-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide

To a solution of4-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide(40 mg, 0.042 mmol) in CH₂Cl₂ (1 mL) was added TFA (16 L). The reactionmixture was stirred for 1 hour and the organic solvent was concentratedunder reduced pressure. To a solution of the resulting mixture in THF(0.3 mL) and MeOH (0.3 mL) was added LiOH.H₂O (17 mg, 0.42 mmol) inwater (0.3 mL). The reaction mixture was stirred for 2 hours at roomtemperature. The organic solvent was removed under reduced pressure andthe aqueous layer was extracted with ethyl acetate. The organic extractswere washed with brine, dried over MgSO₄, celite filtered andconcentrated under reduced pressure. The crude product was purified byPrep HPLC and acetonitrile was removed under reduced pressure. Theremained water was freeze-dried to afford TFA salt formed title compound(21 mg, 71% yield). MS m/z: 581 [M+1].

Additional compounds made by the synthetic route of Example 9 are foundin FIGS. 9A to 9C.

Example 104-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-(isopropylthio)-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide

A.4-(isopropylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

To a solution of4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(500 mg, 1.61 mmol) in dioxane (5 mL) were added K₂CO₃ (668 mg, 4.83mmol) and 2-propanethiol (0.3 mL, 3.22 mmol). The reaction mixture wasstirred for overnight for 70° C. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was separated and theaqueous layer was extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over MgSO₄, celite filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography using (5% to 20% Ethyl acetate/Hexane) as a solventto afford title compound (320 mg, 56% yield). MS m/z: [M+1].

B.4-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-(isopropylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide

4-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-(isopropylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide(46 mg, 71% yield) was prepared as described for Example 9-C startingfrom4-(isopropylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(30 mg, 0.085 mmol). MS m/z: 755 [M+1].

C.4-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-(isopropylthio)-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide

4-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-(isopropylthio)-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide(18 mg, 52% yield) was prepared as described for Example 9-D startingfrom4-((4-ethylpiperazin-1-yl)methyl)-N-(3-((4-(isopropylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methylamino)-4-methylphenyl)-3-(trifluoromethyl)benzamide(35 mg, 0.046 mmol). MS m/z: 625 [M+1].

Additional compounds made by the synthetic route of Example 10 are foundin FIGS. 10A to 10B.

Example 11(E)-3-(2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide

A.4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-pyrrolo[2,3-b]pyridine

To a solution methyltriphenylphosphonium iodide (782 mg, 1.93 mmol) indried THF (5 mL) was added 2.5 M n-BuLi in Hexane (0.74 mL, 1.85 mmol)at −78° C. After 10 minutes,4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde(493 mg, 1.61 mmol) was added to the reaction mixture. The reactionmixture was warmed to room temperature spontaneously. After 2 hours, thereaction mixture was quenched with water and was partitioned betweenethyl acetate and water. The organic layer was separated and the aqueouslayer was extracted with ethyl acetate. The combined organic extractswere washed with brine, dried over MgSO₄, celite filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography using (5% to 15% Ethyl acetate/Hexane) as a solventto afford title compound (371 mg, 76% yield). ¹H NMR (600 MHz, CDCl₃) δ8.40 (s, 1H), 7.27 (d, J=3.6 Hz, 1H), 7.07 (dd, J=11.4, 18 Hz, 1H), 6.78(d, J=3.6 Hz, 1H), 5.78 (d, J=18 Hz, 1H), 5.70 (s, 2H), 5.30 (d, J=11.4Hz, 1H), 4.38 (s, 3H), 3.60 (t, J=8.4 Hz, 2H), 0.97 (t, J=8.4 Hz, 2H), 0(s, 9H). MS m/z: 305 [M+1].

B. (E)-ethyl3-(2-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzoate

(E)-ethyl3-(2-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzoate(302 mg, 58% yield) was prepared as described for Example 5-C startingfrom4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-5-vinyl-1H-pyrrolo[2,3-b]pyridine(340 mg, 1.12 mmol) and ethyl 3-iodo-4-methylbenzoate (360 mg, 1.24mmol). ¹H NMR (600 MHz, CDCl₃) δ 8.52 (s, 1H), 8.35 (d, J=1.2 Hz, 1H),7.87 (dd, J=1.8, 7.8 Hz, 1H), 7.45 (d, J=16.2 Hz, 1H), 7.34 (d, J=16.2Hz, 1H), 7.31-7.27 (m, 2H), 6.81 (d, J=3.6 Hz, 1H), 5.71 (s, 2H), 4.45(q, J=7.2 Hz, 2H), 4.43 (s, 3H), 3.62 (t, J=8.4 Hz, 2H), 2.51 (s, 3H),1.46 (t, J=7.2 Hz, 3H), 0.97 (t, J=8.4 Hz, 2H), 0 (s, 9H). MS m/z: 467[M+1].

C.(E)-3-(2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzoicacid

To a solution of (E)-ethyl3-(2-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzoate(298 mg, 0.64 mmol) in CH₂Cl₂ (2 mL) was added TFA (0.24 mL, 3.19 mmol).The reaction mixture was stirred for 1 hour and the organic solvent wasconcentrated under reduced pressure. To a solution of the resultingmixture in THF (2 mL) and MeOH (2 mL) was added LiOH.H₂O (535 mg, 0.42mmol) in water (2 mL). The reaction mixture was stirred for 8 hours atroom temperature. To a reaction mixture was added 1N HCl solution toproduce solid. The solid product was filtered and dried with nitrogengas flow. The title product (128 mg, 65% yield) was used without furtherpurification. MS m/z: 309 [M+1].

D.(E)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzamide

To a solution of(E)-3-(2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)vinyl)-4-methylbenzoicacid (20 mg, 0.064 mmol) in DMF (1 mL) were added HATU (73 mg, 0.19mmol), DIEA (56 L, 0.32 mmol) and4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzenamine (18 mg,0.064 mmol). The reaction mixture was stirred for overnight at 60° C.after which, it was partitioned between ethyl acetate and water. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated. The crude product waspurified by Prep HPLC and acetonitrile was removed under reducedpressure. The remained water was freeze-dried to afford TFA salt formedtitle compound (23 mg, 51% yield). ¹H NMR (600 MHz, CD₃OD) δ 8.31 (s,1H), 8.17 (d, J=1.8 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.91 (dd, J=1.8,8.4 Hz, 1H), 7.71-7.67 (m, 2H), 7.41 (d, J=16.8 Hz, 1H), 7.32 (d, J=16.2Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 6.78 (d, J=3.6Hz, 1H), 4.35 (s, 3H), 3.61 (s, 2H), 2.60-2.40 (m, 13H), 1.08 (t, J=7.2Hz, 3H). MS m/z: 578 [M+1].

Additional compounds made by the synthetic route of Example 11 are foundin FIGS. 11A to 11B.

Example 125-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide

A.5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-1-naphthoicacid

To a solution of6-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(400 mg, 1.22 mmol) in DMSO (4 mL) were added K₂CO₃ (507 mg, 3.67 mmol)and 5-hydroxy-1-naphthoic acid (230 mg, 1.22 mmol). The reaction mixturewas stirred for overnight at 100° C. after which, It was cooled to roomtemperature. To the reaction mixture was added 1N HCl solution to reachpH=5. The produced solid was filtered and dried nitrogen gas flow. Thetitle compound (380 mg, 66% yield) was used next reaction withoutfurther purification. MS m/z: 469 [M+1].

B.5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide

5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide(92 mg, 88% yield) was prepared as described for Example 11-D startingfrom5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-1-naphthoicacid (80 mg, 0.17 mmol) and 3-(trifluoromethyl)benzenamine (55 mg, 0.34mmol). MS m/z: 612 [M+1].

C.5-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide

5-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide(48 mg, 71% yield) was prepared as described for Example 9-D startingfrom5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide(85 mg, 0.14 mmol). MS m/z: 482 [M+1].

D.5-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide

5-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide(9 mg, 32% yield) was prepared as described for Example 8 starting from5-(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide(30 mg, 0.062 mmol). MS m/z: 448 [M+1].

Additional compounds made by the synthetic route of Example 12 are foundin FIGS. 12A to 12D.

Example 135-(6-(4-(piperazin-1-ylsulfonyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide

A. tert-butyl4-(4-(4-(5-(3-(trifluoromethyl)phenylcarbamoyl)naphthalen-1-yloxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenylsulfonyl)piperazine-1-carboxylate

tert-butyl4-(4-(4-(5-(3-(trifluoromethyl)phenylcarbamoyl)naphthalen-1-yloxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenylsulfonyl)piperazine-1-carboxylate(42 mg, 70% yield) was prepared as described for Example 5-B startingfrom5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide(40 mg, 0.065 mmol) and tert-butyl4-(4-aminophenylsulfonyl)piperazine-1-carboxylate (22 mg, 0.065 mmol).MS m/z: 917 [M+1].

B.5-(6-(4-(piperazin-1-ylsulfonyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide

5-(6-(4-(piperazin-1-ylsulfonyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide(22 mg, 64% yield) was prepared as described for Example 9-D startingfrom tert-butyl 4-(4-(4-(5-(3-(trifluoromethyl)phenylcarbamoyl)naphthalen-1-yloxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenylsulfonyl)piperazine-1-carboxylate (40 mg, 0.043 mmol). MS m/z: 687 [M+1].

Additional compounds made by the synthetic route of Example 13 are foundin FIG. 13.

Example 14 Additional Compounds

The following compounds were made in a manner similar to the synthesisfound in Example 6.

¹H NMR, and Structure Name or MS (m/z)

4-methoxy-N-(2-methyl-5-((3- (trifluoromethyl)phenyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide ¹H NMR (600 MHz, DMSO-d₆) δ11.98 (s, 1H), 10.52 (s, 1H), 9.80 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H),8.24 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.72  1 (dd, J = 1.2, 7.8 Hz,1H), 7.59 (t, J = 7.8 Hz, 1H), 7.47- 7.43 (m, 3H), 6.93 (s, 1H), 4.46(s, 3H), 2.41 (s, 3H). MS m/z: 469 [M + 1]

   2 4-methoxy-N-(2-methyl-5-((4-((4- methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide MS m/z: 581 [M + 1]

   3 N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)- 2-methylphenyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine-5-carboxamide MS m/z: 595 [M + 1]

   4 3-((1H-pyrrolo[2,3-b]pyridin- 4-yl)oxy)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide MS m/z: 412 [M + 1]

   5 3-((1H-pyrrolo[2,3-b]pyridin- 4-yl)oxy)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5- (trifluoromethyl)phenyl)benzamide MSm/z: 492 [M + 1]

   6 3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)- 4-methylbenzamide MS m/z: 539[M + 1]

   7 3-((1H-pyrrolo[2,3-b]pyridin- 4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)benzamide MS m/z: 524 [M + 1]

   8 4-((1H-pyrrolo[2,3-b]pyridin- 4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)- 3-methylbenzamide MS m/z: 538[M + 1]

   9 N-(3-((1H-pyrrolo[2,3-b]pyridin- 4-yl)oxy)-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)- 3-(trifluoromethyl)benzamide MS m/z:538 [M + 1]

  10 N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl- 3-((2-(methylamino)pyrimidin-4-yl)oxy)benzamide MS m/z: 529 [M + 1]

  11 3-((1H-pyrazolo[3,4-d]pyrimidin- 4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)- 4-methylbenzamide MS m/z: 540[M + 1]

  12 N-(4-((4-ethylpiperazin-1-yl)methyl)- 3-(trifluoromethyl)phenyl)-4-methyl-3-((3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)oxy)benzamideMS m/z: 554 [M + 1]

  13 N-(4-((4-ethylpiperazin-1-yl)methyl)- 3-(trifluoromethyl)phenyl)-4-methyl-3-((6-methyl-7H- pyrrolo[2,3-d]pyrimidin-4- yl)oxy)benzamide MSm/z: 553 [M + 1]

  14 4-(5-((4-((4-ethylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)- 2-methylphenoxy)-N-methylpicolinamide MS m/z: 556 [M + 1]

  15 N-(4-((4-ethylpiperazin-1-yl)methyl)- 3-(trifluoromethyl)phenyl)-3-((3-(methoxymethyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-4-methylbenzamide MS m/z: 582 [M + 1]

  16 3-((6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)- 4-methylbenzamide MS m/z: 572 [M + 1]

  17 3-((9H-purin-6-yl)oxy)-N-(4-((4- ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)- 4-methylbenzamide MS m/z: 540 [M + 1]

  18 3-((6,7-dimethoxyquinazolin-4- yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)- 4-methylbenzamide MS m/z: 610[M + 1]

  19 3-((7H-pyrrolo[2,3-d]pyrimidin- 4-yl)thio)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)benzamide MS m/z: 541 [M + 1]

  20 1-(3-((7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxy)-4-methylphenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)urea MS m/z:554 [M + 1]

  21 3-((7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-4- methylbenzamide MS m/z: 471 [M + 1]

  22 3-((7H-pyrrolo[2,3-d]pyrimidin- 4-yl)oxy)-4-methyl-N-(3-methyl-4-((4-methylpiperazin-1- yl)methyl)phenyl)benzamide MS m/z: 471 [M + 1]

Example 15 B-Raf Cell Proliferation Assay

Ba/F3 cells and B-RAF transformed Ba/F3 cells were maintained in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) in a 5% CO2incubator at 37° C. The untransformed Ba/F3 cells are supplemented with1.0 ng/ml of recombinant IL3. 4000 Ba/F3 cells per well were plated inquadruplicate in 384-well plates, in RPMI 1640 media supplemented with10% FBS and various concentrations of IL3. After 48 h of growth,Brightglo reagent (Promega, Wis.) was added to each well. Luminescentwas read as counts/sec. XL-fit was used for IC50 analysis.

XI-1 Inhibits Phosphorylation of JNK and p38 but not Erk1/2 FollowingStimulation with Anisomycin.

AZD628 is a potent pan-b-raf inhibitor, PLX4720 is a selective b-rafinhibitor, BAY61-3036 is a reported Syk kinase inhibitor

Phosphorylation Analysis

The phosphorylation levels of Erk, JNK, and p38 were assessed by westernblotting using phospho-specific antibodies (results not shown). Inbrief, cells were treated for 15 min with/without 2 uM anicomycin tostimulate the MAPK-signaling pathways. Next various concentrations ofthe test compound were added to treat cells for 90 minutes. Cells lysedin lysis buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 5 mM EDTA, 1 mMEGTA, 1% Nonidet P-40, 2 mM Na3VO4 and protease inhibitor cocktail(Roche)). Equal amounts of lysate (50 g) were subjected to SDS-PAGEfollowed by immunoblotting with phospho-specificantibodies—anti-phospho-Erk (Thr202/Tyr204), anti-phospho-JNK(Thr183/Tyr185) and anti-phospho-p38 (Thr180/Tyr182) antibodies—orantibodies recognizing Erk (Cell signaling). Proteins were detected byenhanced chemioluminescence (ECL-plus; Amersham), following themanufacturer's guidelines.

INCORPORATION BY REFERENCE

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended with be encompassed by the following claims.

What is claimed:
 1. A compound of formula I:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein, ring D is aryl or heteroaryl; R is H, halo, or -A-B; A isNR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), NR_(A)C(O)NR_(A), orabsent; B is H, alkyl, alkoxy, cycloalkyl, or aryl, each of which isoptionally substituted; R₁ is hydroxyl, alkyl, alkoxy, C(O)OR_(A),C(O)NR_(A)R_(B), or NR_(A)R_(B), each of which may be optionallysubstituted; or H or halo; R′ is absent, or R and R′ together with theatoms to which each is attached, form a cycloalkyl, heterocycloalkyl,aryl, or heteroaryl ring, each of which is optionally substituted; Z isNR_(A), O, NR_(A)C(O), C(O)NR_(A), CR₃R₄ or S(O)_(m); R₃ is H or alkyl;R₄ is H, alkyl, or absent; or R₃ and R₄ together with the carbon towhich each is attached form C(O); ring E is monocyclic or bicyclicheteroaryl; R_(z) is NR_(A)R₂; R₂ is H, optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheterocycloalkyl, C(O)R_(A), C(O)OR_(A), C(O)NR_(A)R_(B),C(NR_(B))R_(A), or C(NR_(B))OR_(A); R₅ is H, halo, alkyl, alkoxy, orthioalkoxy; R₆ is H, NR_(A)R_(B), or OR_(A); each R_(A) is independentlyH, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each ofwhich may be optionally substituted; each R_(B) is independently H,alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each ofwhich may be optionally substituted; or, for each occurrence ofNR_(A)R_(B), R_(A) and R_(B) are taken together with the nitrogen atomto which they are attached to form a 3-7 membered heterocycloalkyl ring;each m is independently 0, 1, or 2; and each n is independently 0 or 1.2. The compound of claim 1, wherein ring D is selected from phenyl,naphthyl, tetrahydronaphthyl, indanyl, idenyl, pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, pyrrolo pyridinyl, thiazolo pyridinyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, indazolyl, indolonyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzooxazolyl, and quinoxalinyl.
 3. The compound ofclaim 2, wherein ring D is selected from phenyl, naphthyl, pyrazinyl,pyrimidinyl, pyrrolo pyridinyl, thiazolo pyridinyl, indazolyl,indolonyl, and quinolinyl.
 4. The compound of claim 1, wherein ring E isselected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl,pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, isooxazolyl, thiophenyl, furanyl, indazolyl,indolonyl, quinolinyl, isoquinolinyl, quinazolinyl,1H-pyrrolo[2,3-b]pyridine, 9H-purine, 7H-pyrrolo[2,3-d]pyrimidine,1H-pyrazolo[3,4-d]pyrimidine, and quinoxalinyl.
 5. The compound of claim4, wherein ring E is selected from phenyl, naphthyl, pyridinyl,pyrazinyl, and pyrimidinyl.
 6. The compound of claim 1, of formula II:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein, Z is NH or O; R is H or -A-B; A is NR_(A)C(O), O, S(O)_(m),C(O), C(O)O, C(O)NR_(A), or absent; B is alkyl, alkoxy, or aryl, each ofwhich is optionally substituted; R₁ is H, alkyl, alkoxy, or halo; eachof which may be optionally substituted; R₂ is H, C(O)R_(A), C(O)OR_(A),C(O)NR_(A)R_(B), C(NR_(B))R_(A), or C(NR_(B))OR_(A); each R_(A) isindependently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl orheteroaryl, each of which may be optionally substituted; each R_(B) isindependently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl orheteroaryl, each of which may be optionally substituted; and m is 0, 1,or
 2. 7. The compound of claim 6, wherein R₂ is H, C(O)R_(A),C(O)OR_(A), or C(O)NR_(A)R_(B).
 8. The compound of claim 7, wherein eachR_(A) is independently H, alkyl, or cycloalkyl, each of which may beoptionally substituted; and R_(B) is H.
 9. The compound of claim 6,wherein R₂ is H,


10. The compound of claim 6, wherein R₁ is H, alkyl, alkoxy, or halo.11. The compound of claim 10, wherein R₁ is H, methyl, methoxy, orchloro.
 12. The compound of claim 6, wherein R is H or -A-B; A isNR_(A)C(O), C(O), C(O)O, C(O)NR_(A), or absent; and B is alkyl, alkoxy,or aryl, each of which is optionally substituted.
 13. The compound ofclaim 12, wherein A is NHC(O), C(O)O, C(O)NH, or absent.
 14. Thecompound of claim 12, wherein B is phenyl, methyl, or methoxy; each ofwhich is optionally substituted.
 15. The compound of claim 14, wherein Bis optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or hydroxyl,each of which is optionally substituted.
 16. The compound of claim 12,wherein R is selected from H, methyl, methoxy,


17. The compound of claim 1, of formula III:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein, ring D is aryl or heteroaryl; R is H, halo, or -A-B; A isNR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), or absent; B is H,alkyl, cycloalkyl, or aryl, each of which is optionally substituted; R₁is H, hydroxyl, alkyl, alkoxy, C(O)OR_(A), C(O)NR_(A)R_(B), NR_(A)R_(B),or halo; each of which may be optionally substituted; or R and R′together with the atoms to which each is attached, form a cycloalkyl,heterocycloalkyl, aryl, or heteroaryl ring, each of which is optionallysubstituted; R₂ is H, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl,C(O)R_(A), C(O)OR_(A), C(O)NR_(A)R_(B), C(NR_(B))R_(A), orC(NR_(B))OR_(A); each R_(A) is independently H, alkyl, alkenyl,cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may beoptionally substituted; each R_(B) is independently H, alkyl, alkenyl,cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may beoptionally substituted; and m is 0, 1, or
 2. 18. The compound of claim17, wherein R₂ is H, optionally substituted aryl, or optionallysubstituted heteroaryl.
 19. The compound of claim 18, wherein R₂ is H,phenyl, pyridyl, pyrimidinyl, each of which is optionally substituted.20. The compound of claim 19, wherein R₂ is H,


21. The compound of claim 17, wherein ring D is phenyl, pyrrolopyridine, benzothiazole, indazole, pyrazine, or indolinone.
 22. Thecompound of claim 17, wherein R₁ is H, hydroxyl, alkyl, NR_(A)R_(B), orhalo; each of which may be optionally substituted.
 23. The compound ofclaim 17, wherein R is H, halo, or -A-B; A is NR_(A)C(O), O, S(O)_(m),C(O), C(O)O, C(O)NR_(A), or absent; and B is alkyl, cycloalkyl, or aryl,each of which is optionally substituted.
 24. The compound of claim 23,wherein A is NHC(O), C(O)O, C(O)NH, or absent.
 25. The compound of claim23, wherein B is H, alkyl, cycloalkyl, or aryl, each of which isoptionally substituted.
 26. The compound of claim 25, wherein B isoptionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, alkoxy,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, or hydroxyl, eachof which is optionally substituted.
 27. The compound of claim 23,wherein R is H, methyl, Cl, F, COOH, C(O)NHCH₃,


28. The compound of claim 1, of formula IV:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein, R is H or -A-B; A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O,C(O)NR_(A), or absent; B is alkyl or aryl, each of which is optionallysubstituted; R₁ is H, alkyl, alkoxy, or halo; each of which may beoptionally substituted; Z is NR_(A), O, or S(O)_(m); R₃ is H or alkyl;R₄ is H or alkyl; or R₃ and R₄ together with the carbon to which each isattached form C(O); R₅ is H, halo, alkoxy, or thioalkoxy, each R_(A) isindependently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl orheteroaryl, each of which may be optionally substituted; and each m isindependently 0, 1, or
 2. 29. The compound of claim 28, wherein Z isNR_(A) or O; R₃ is H; R₄ is H; or R₃ and R₄ together with the carbon towhich each is attached form C(O).
 30. The compound of claim 29, whereinZ is NH or O.
 31. The compound of claim 28, wherein R₅ is H, halo,alkoxy, or thioalkoxy.
 32. The compound of claim 31, wherein R₅ is H,Cl, methoxy, or S(i-Pr).
 33. The compound of claim 28, wherein R₁ is H,alkyl, or alkoxy; each of which may be optionally substituted.
 34. Thecompound of claim 28, wherein R is -A-B; A is NR_(A)C(O) or C(O)NR_(A);and B is alkyl or aryl, each of which is optionally substituted.
 35. Thecompound of claim 28, wherein A is NHC(O) or C(O)NH.
 36. The compound ofclaim 28, wherein B is alkyl or aryl, each of which is optionallysubstituted.
 37. The compound of claim 36, wherein B is optionallysubstituted with alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, halo, or hydroxyl, each of which isoptionally substituted.
 38. The compound of claim 28, wherein R is


39. The compound of claim 1, of formula V:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein, R is H or -A-B; A is NR_(A)C(O), O, S(O)_(m), C(O), C(O)O,C(O)NR_(A), or absent; B is alkyl or aryl, each of which is optionallysubstituted; R₁ is H, alkyl, alkoxy, or halo; each of which may beoptionally substituted; R₅ is H, halo, alkoxy, or thioalkoxy, each R_(A)is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl orheteroaryl, each of which may be optionally substituted; and m is 0, 1,or
 2. 40. The compound of claim 39, wherein R₅ is halo or alkoxy. 41.The compound of claim 40, wherein R₅ is Cl or methoxy.
 42. The compoundof claim 39, wherein R₁ is alkyl, which may be optionally substituted.43. The compound of claim 39, wherein R is -A-B; A is NR_(A)C(O) orC(O)NR_(A); and B is alkyl or aryl, each of which is optionallysubstituted.
 44. The compound of claim 43, wherein A is NHC(O) orC(O)NH.
 45. The compound of claim 43, wherein B is alkyl or aryl, eachof which is optionally substituted.
 46. The compound of claim 45,wherein B is optionally substituted with alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo,or hydroxyl, each of which is optionally substituted.
 47. The compoundof claim 39, wherein R is


48. The compound of claim 1, of formula VI:

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein, ring D is aryl or heteroaryl; R is H, halo, or -A-B; A isNR_(A)C(O), O, S(O)_(m), C(O), C(O)O, C(O)NR_(A), or absent; B is alkyl,cycloalkyl, or aryl, each of which is optionally substituted; R₁ is H,hydroxyl, alkyl, alkoxy, C(O)OR_(A), C(O)NR_(A)R_(B), NR_(A)R_(B), orhalo; each of which may be optionally substituted; R₆ is H, NR_(A)R_(B),or OR_(A); R₅ is H, halo, alkoxy, or thioalkoxy, each R_(A) isindependently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl orheteroaryl, each of which may be optionally substituted; each R_(B) isindependently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl orheteroaryl, each of which may be optionally substituted; and m is 0, 1,or
 2. 49. The compound of claim 48, wherein R₆ is H or NR_(A)R_(B). 50.The compound of claim 49, wherein R_(A) is an optionally substitutedaryl and R_(B) is H.
 51. The compound of claim 48, wherein R₅ is H orCl.
 52. The compound of claim 48, wherein ring D is phenyl, naphthyl,indolonyl, or quinolinyl.
 53. The compound of claim 52, wherein R₁ is H.54. The compound of claim 53, wherein R is -A-B; A is NR_(A)C(O) orC(O)NR_(A); and B is alkyl or aryl, each of which is optionallysubstituted.
 55. The compound of claim 54, wherein A is NHC(O) orC(O)NH.
 56. The compound of claim 54, wherein B is alkyl or phenyl, eachof which is optionally substituted.
 57. The compound of claim 56,wherein B is optionally substituted with alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo,or hydroxyl, each of which is optionally substituted.
 58. The compoundof claim 54, wherein R is


59. The compound of claim 1, selected from a compound in any one ofTables 1-13.
 60. A pharmaceutical composition comprising a compound ofclaim 1, or a pharmaceutically acceptable ester, salt, or prodrugthereof, together with a pharmaceutically acceptable carrier.
 61. Amethod of inhibiting a b-raf kinase in a subject, comprisingadministering administering to the subject a compound of formula I. 62.The method of claim 61, wherein the b-raf kinase is a mutant b-rafkinase.
 63. The method of claim 62, wherein the mutation of the mutantb-raf kinase is V600E, T529I, or V600E/T529I.
 64. A method of treating adisease related to kinase modulation in a subject comprisingadministering to the subject a compound or pharmaceutically acceptablesalt of formula I; wherein the kinase is selected from b-raf, Abl,Csf1R, EGFR, EphA8, FGFR1,2,3,4, FLT3, KIT, Lok, MAP4K1, MUSK, p38alpha,beta, PDGFRalpha, beta, Ret, Taok3, TNNI3K, Fes, Lyn SRPK1, STK36, TIE2,DDR1, EPHA2, ROIK1, RIOK3, NKF1LK, Src, Tak1, BLK, EphA4, EphB2, Fgr,FLT4, MAP4K2, ANKK1, Frk, Lck, Map4K5, Erbb4, Map4k4, MKNK2, Tec, Flt1,Hck, Tnk2, Txk, BTK, SLK, RiPK1, RIPK2, BIKE, CIT, CDKL2, DRAK, EphB1,JNK2, MLK1, MYLK2, TrkA,B,C, VEGFR2, IKKalpha, PTK2B, MAP4K3, Tie2, Fyn,Zak, DDR2, AurC, Lyn, Hpk1, and Gck.
 65. The method of claim 64, whereinthe kinase is selected from b-raf b-raf, Abl, Csf1R, EGFR, EphA8,FGFR1,2,3,4, FLT3, KIT, Lok, MAP4K1, MUSK, p38alpha, beta, PDGFRalpha,beta, Ret, Taok3, TNNI3K, Fes, Lyn SRPK1, STK36, TIE2, DDR1, EPHA2,ROIK1, RIOK3, NKF1LK, Src, Tak1, BLK, EphA4, EphB2, Fgr, FLT4, MAP4K2,ANKK1, Frk, Lck, Map4K5, Erbb4, Map4k4, MKNK2, Tec, Flt1, Hck, Tnk2,Txk, BTK, SLK, RiPK1, RIPK2, BIKE, CIT, CDKL2, DRAK, EphB1, JNK2, MLK1,MYLK2, TrkA,B,C, VEGFR2, IKKalpha, PTK2B, MAP4K3, Tie2, Fyn, Zak, DDR2,AurC, Lyn, Hpk1, and Gck.
 66. A method of treating a disease related tob-raf or b-raf mutation modulation in a subject comprising administeringto the subject a compound or pharmaceutically acceptable salt of formulaI.
 67. A method of treating a disease related to b-raf or b-raf mutationmodulation in a subject comprising: administering to the subjectidentified as in need thereof a compound or pharmaceutically acceptablesalt of formula I.
 68. The method of claim 66 or 67, wherein themodulation is inhibition.
 69. The method of claim 66 or 67, wherein theb-raf mutation is V600E, T529I, or V600E/T529I.
 70. The method of claim66 or 67 wherein the disease is cancer or a proliferation disease. 71.The method of claim 70, wherein the disease is melanoma, lung cancer,colon cancer, breast cancer, prostate cancer, liver cancer, pancreascancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer,skin cancer, bone cancer, gastric cancer, breast cancer, pancreaticcancer, glioma, gliobastoma, hepatocellular carcinoma, papillary renalcarcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas,myelomas, and solid tumors.
 72. The method of claim 66 or 67, whereinthe subject is administered an additional therapeutic agent.
 73. Themethod of claim 72, wherein the compound and the additional therapeuticagent are administered simultaneously or sequentially.
 74. The method ofclaim 72, wherein the additional therapeutic is a b-raf inhibitor. 75.The method of claim 72, wherein the additional therapeutic is a clinicalb-raf inhibitor that directly targets the b-raf ATP site.
 76. The methodof claim 75, wherein the additional therapeutic is sorafenib, Raf265,AZ628, PLX-4032, PLX-4720, gefitinib, erlotinib, lapatinib, XL-647,HKI-272, BIBW2992, AV-412, CI-1033, PF00299804, BMS 690514, cetuximab,panitumumab, or matuzumab.
 77. A method of treating a disease related tob-raf or b-raf mutation modulation in a subject, wherein the disease isresistant to drug resistant mutations in b-raf, comprising administeringto the subject a compound or pharmaceutically acceptable salt of formulaI.
 78. The method of claim 76, wherein the b-raf mutation is V600E,T529I, or V600E/T529I.
 79. A method of treating cancer in a subject,wherein the cancer comprises b-raf activated tumors, comprisingadministering to the subject a compound or pharmaceutically acceptablesalt of formula I.
 80. A method of treating cancer in a subject, cancercomprises b-raf activated tumors, wherein the subject is identified asbeing in need of b-raf inhibition for the treatment of cancer,comprising administering to the subject a compound or pharmaceuticallyacceptable salt of formula I.
 81. The method of claim 79 or 80, whereinthe disease is melanoma, lung cancer, colon cancer, breast cancer,prostate cancer, liver cancer, pancreas cancer, brain cancer, kidneycancer, ovarian cancer, stomach cancer, skin cancer, bone cancer,gastric cancer, breast cancer, pancreatic cancer, glioma, gliobastoma,hepatocellular carcinoma, papillary renal carcinoma, head and necksquamous cell carcinoma, leukemias, lymphomas, myelomas, and solidtumors.
 82. The method of any one of claims 61-81, wherein the subjectis a human.
 83. A kit comprising a compound or pharmaceuticallyacceptable salt of formula I capable of inhibiting b-raf or b-rafmutation activity; and instructions for use in treating cancer.